FDA Lifts Hold on bluebird bio’s Sickle Cell and Beta-Thalassemia Gene Therapies – BioSpace

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The U.S. Food and Drug Administration (FDA)liftedthe clinical holds on bluebird bios Phase I/II HGB-206 and Phase III HGB-210 studies of LentiGlobin for sickle number disease gene therapy for adults and children and the Phase III Northstar-2 and Northstar-3 trials of betibeglogene autotemcel gene therapy (Zynteglo in the EU and UK) for adults, adolescents and children with transfusion-dependent beta-thalassemia (TDT).

On February 16, bluebird bioplacedits Phase I/II and Phase III trial of LentiGlobin for SCD on temporary suspensions because of a case of acute myeloid leukemia (AML). Another patient from Group C of HGB-206 was suspected of myelodysplastic syndrome (MDS).

LentiGlobin is a gene therapy, which has been granted Orphan Drug Designation, Fast Track Designation, Regenerative Medicine Advanced Therapy (RMAT) Designation, and Rare Pediatric Disease Designation. The Suspected Unexpected Serious Adverse Reaction (SUSAR) was assumed to be linked to the viral vector used to deliver their genetic payloads in the gene therapies.

On April 20, theyreviseda previously reported case of myelodysplastic syndrome (MDS) in its Phase I/II trial of LentiGlobin for SCD but have now decided it is not a case of MDS and revised it to transfusion-dependent anemia.

At the time, Philip Gregory, bluebird bios chief scientific officer, stated, In addition to our earlier findings of several well-known genetic mutations and gross chromosomal abnormalities commonly observed in AML in this patient, our latest analyses identified the integration site for the vector within a gene called VAMP4. VAMP4 has no known association with the development of AML nor with processes such as cellular proliferation or genome stability."

"Moreover, we see no significant gene misregulation attributable to the insertion event. In totality, the data from our assessments provide important evidence demonstrating that it is very unlikely our BB305 lentiviral vector played a role in this case, and we have shared with theFDAthat we believe these results support lifting the clinical holds on our beta-thalassemia and sickle cell disease programs, Gregory said.

Betibeglogene autotemcel (beti-cel) is a one-time gene therapy that adds function copies of a modified form of the beta-globin gene to a patients own hematopoietic stem cells. This has been granted conditional marketing authorization (CMA) under the brand name Zynteglo for patients 12 years and older with TDT in Europe and the UK. It is apparently on hold there while the European Medicines Agency (EMA)s Pharmacovigilance Risk Assessment Committee (PRAC) reviews the therapys safety. The CMA remains valid while the renewal application review is ongoing.

Patient safety continues to be our utmost priority, and we are grateful for the close partnership with the FDA, investigators, scientists and most importantly, patients, who all contributed to the assessments of the adverse events in HGB-206 that ultimately led to todays announcement, said Andrew Obenshain, president, severe genetic diseases, bluebird bio.

"As pioneers in gene therapy, we remain committed to advancing the field through our learnings. Over the past four months, we have gained deeper knowledge and understanding of the pathophysiology of sickle cell disease that will allow us to better serve patients and the broader community," Obenshain continued. "We look forward to resuming our clinical programs and continuing to advance toward major regulatory submissions for sickle cell disease and beta-thalassemia.

Bluebird plans to continue its rolling Biologics License Application (BLA) to the FDA for beti-cel in mid-2021 for adults, adolescents, and children with transfusion dependent beta-thalassemia across all genotypes.

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Abecma Continues to Improve Survival in Heavily Pretreated Patients With Multiple Myeloma – Curetoday.com

Abecma (idecabtagene vicleucel ; ide-cel; formerly bb2121), a chimeric antigen receptor (CAR)-T cell therapy, led to improved survival in patients with multiple myeloma who have been treated with many other lines of therapy, according to updated results from the KarMMa trial presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.1

The favorable benefit risk profile of ide-cel, regardless of the number of prior lines of therapy, supports its role as a treatment option for heavily pretreated relapse refractory multiple myeloma, Dr. Larry D. Anderson, associate professor, UT Southwestern Medical Center, said during a presentation of the poster.

At the December 21, 2020, data cutoff, the average follow-up was 24.8 months (range, 1.7-33.6).

Overall response rate (ORR) the percentage of patients who responded to the treatment was 73% in the overall population, including a 33% complete response rate, where disease could not be detected (CRR; complete response [CR] or stringent complete response [sCR]), 20% with a very good partial response (VGPR), and 20% who had a partial response (PR). ORR rates were 50%, 69%, and 81%, respectively, across the 150, 300, and 450 million CAR T cell-dose arms, including CR/sCR rates of 25%, 29%, and 39%.

Of note, ORR did not vary by the number of prior lines of therapy received. For those who received three prior lines of therapy (a total of 15 patients), the ORR was 73%, including a CRR of 53% and VGPR of 20%, compared with an ORR of 73% in those who received four or more (112 patients) lines of therapy, including a CRR of 30%, VGPR of 23%, and PR of 20%.

Average duration of response (DOR; the time patients disease was stable or in remission after being treated) was 10.9 months, including 9.9 months for the 300 million CAR T cells-dose arm and 11.3 months for the 450 million CAR T cells-dose arm -dose arm. Median DOR was 21.5 months in patients who experienced a CR or sCR. Median DOR by response were 21.5 months among those who experienced a CR; 10.4 months for those with VGPR; and 4.5 months in those with PRs.

Moreover, the rate of event-free 24-month DOR appeared to be similar in patients who received three or four or more lines of therapy. For those who received three lines of prior therapy, median DOR was eight months, compared with 10.9 months in those who received four or more lines of therapy.

Average progression-free survival (PFS) meaning the length of time after treatment when the disease does not get worse was 8.6 months across all target doses, including 5.8 months for the 300 million CAR T cells-dose arm and 12.2 months for the 450 million CAR T cells-dose arm -dose arm. Similarly, average PFS was similar among those who previously received three lines of therapy, compared with four or more prior lines of therapy (8.6 months vs 8.9 months, respectively).

On average, it took patients about one month to respond to therapy and about 2.8 months to experience a CR.

Median overall survival (OS) was 24.8 months, including a median OS of 22.0 months in those who received three lines of prior therapy and 25.2 months in those who received four or more lines of prior therapy. Moreover, OS was 20 months or longer across several key high-risk subgroups, including those aged 65 or older (21.7 months), those with extramedullary disease (20.2 months), and those with triple refractory disease (21.7 months).

Regarding side effects, cytokine release syndrome (CRS; the effect of many inflammatory cytokine immune cells being release into the blood stream) and neurotoxicity (brain and/or nervous system damage) rates were similar, regardless of prior lines of therapy received, and were mostly low grade. In total, 85% and 18% of the overall population experienced at least 1 CRS or neurotoxicity event, respectively.

The safety profile of Abecma was consistent with long-term follow-up, with similar rates of infections and secondary primary malignancies, and no unexpected gene therapy related toxicities were observed. The most common grade 3 to 4 side effects in the overall population were neutropenia (89%), anemia (61%), thrombocytopenia (52%), leukopenia (39%), lymphopenia (27%) and infections (27%).

Long-term results from the KarMMA trial continue to demonstrate frequent, deep, and durable responses in heavily pretreated patients with [relapsed/refractory multiple myeloma], the study authors write in the poster. ORR, CRR, DOR and PFS were consistent with previous reports and patients received similar benefit regardless of the number of prior lines of therapy.

In his presentation, Anderson presented data on long-term efficacy and safety following treatment with Abecma in the pivotal phase 2 KarMMa trial (NCT03361748)-including overall data and by prior line of therapy that patients had received (three compared to four or more), since the FDA label is requiring at least four prior lines, and this study only required three, he added.

In total, 140 patients who had received at least three prior lines of therapy for multiple myeloma including an IMiD, a PI, and an anti-CD38 antibody and were refractory to their last treatment regimen, were enrolled in the study. However, only 128 patients received infusion with Abecma.

Patients were treated with Abecma across the target dose range of 150 (four patients), 300 (70 patients), and 450 (54 patients) million CAR T cells.

ORR served as the primary end point of the study. Secondary end points included CRR, safety, DOR, PFS, OS, pharmacokinetics, minimal residual disease, quality of life and health economics and outcomes research.

At the start of the trial, the average patient age was 61 years (range, 33-78) and patients had a median of six years (range, 1-18) since their diagnosis. A majority of the patients were male (59%), had high tumor burden (51%), B-cell maturation antigen (BCMA) expression 50% or more at screening (85%), ECOG performance status which measures how functional a patient is on a range of 1 (fully functioning) to 5 (dead) of 1 (53%), and Revised International Staging System disease stage of II (70%). Thirty-five percent of patients had high-risk features.2

The median number of prior therapies was six (range, 3-16) and 94% had previously undergone at least one autologous hematopoietic stem cell transplant (94%). Eighty-eight percent of patients required bridging therapy, a kind of pre-treatment before CAR-T cell thearpy. Eighty-nine percent of patients had double-refractory disease, 84% were triple-refractory and 26% were penta-refractory.

Patients who had received three prior lines of therapy had similar baseline characteristics, compared with those who received four or more prior lines, including differences in extramedullary disease, high-risk cytogenetics, prior refractoriness and time since the initial diagnosis to screening.

Patients with relapsed/refractory multiple myeloma previously exposed to immunomodulatory agents, protease inhibitors, and anti-CD38 antibodies have poor outcomes with subsequent therapy using previously approved regimens, with expected response rates in the 26% to 31% range, PFS in the two- to four-month range, and overall survival less than nine months, Anderson explained.

However, the BCMA-directed CAR-T cell therapy previously demonstrated favorable tolerability with deep, durable responses in patients who were heavily pretreated with relapsed/refractory multiple myeloma.As a result, the FDA approved the agent for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody, representing the first BCMAdirected CAR T-cell therapy approved.

The study authors noted that is being explored in ongoing clinical trials, including the following:

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HSCT-Sparing, Chemotherapy-Free Treatment of Ph+ ALL With Ponatinib/Blinatumomab Leads to 100% CR Rate – Cancer Network

Combination therapy with ponatinib (Iclusig) and blinatumomab (Blincyto) induced a complete response in all patients with Philadelphia chromosome (Ph)positive acute lymphocytic leukemia (ALL) who were treated on a phase 2 study (NCT03263572), according to a presentation at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.1

The chemotherapy-free, hematopoietic stem cell transplant (HSCT)sparing regimen for patients receiving systemic therapy in the first-line (n = 20) led to a complete response (CR) rate or pathologic CR rate of 100%, while patients with relapsed/refractory Phpositive ALL had a rate of 89%. Moreover, patients in the frontline Phpositive cohort had a major molecular response (MMR) of 100% and a complete molecular response (CMR) of 85%.

The combination of ponatinib and blinatumomab is safe and effective in Ph-positive ALL, Nicholas James Short, MD, an assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said during an oral presentation of the data. Overall, the novel chemotherapy-free combination of ponatinib and blinatumomab appears to be a promising regimen in both frontline and relapsed/refractory Ph-ALL, as well as in chronic myeloid leukemia in lymphoid blast phase [CML-LBP]. Given the particularly favorable outcomes of newly diagnosed patients with frontline, Ph-positive ALL who were not transplanted in first remission, these data suggest that this regimen may serve as an effective transplant-sparing regimen in this population.

Chemotherapy plus a TKI has become the standard of care in newly diagnosed Ph-positive ALL, with first- and second-generation TKIs yielding 5-year overall survival (OS) rates of approximately 35% to 50%.2-4 Moreover, while ponatinib has yielded promising activity in patients with T315I mutations, which are present in up to 75% of patients at relapse,5 blinatumomab has demonstrated efficacy as a monotherapy in the relapsed/refractory setting, and in combination with dasatinib in newly diagnosed patients.6,7

The trial enrolled patients with newly diagnosed or relapsed/refractory Ph-positive ALL, as well as lymphoid accelerated or blast phase CML. Patients who had previously received 1 to 2 courses of chemotherapy with or without a TKI were able to enroll in the newly diagnosed cohort. Additionally, patients needed to be over 18 years of age, with a ECOG performance status of 0-1, and adequate hepatic function in order to enroll.

Patients with uncontrolled or active cardiovascular disease, including a history of myocardial infarction, cardiovascular accident, or revascularization within 3 months; congestive heart failure with reduced left ventricular ejection fraction; atrial of ventricular arrhythmia; a history of arterial or venous thromboembolism; or uncontrolled hypertension were not able to enroll on the study. Additional exclusion criteria included significant central nervous system (CNS) pathology with the exception of CNS leukemia.

Patients received a 30 mg induction dose of ponatinib and a standard dose of blinatumomab on a 4 weeks on, 2 weeks off schedule. From there, patients received up to 4 consolidation cycles of the regimen followed by maintenance ponatinib for 5 years, the dose of which decreased to 15 mg daily once patients achieved a CMR. All patients were given 12 doses of intrathecal chemotherapy with an altering administration of cytarabine and methotrexate.

The primary of end point of the trial was CMR rate in the frontline cohort, and CR/pathologic CR rate in the relapsed/refractory setting. Key secondary end points included event-free survival (EFS), OS, and safety.

To date, 20 frontline patients have been treated, 10 with relapsed/refractory disease, and 5 with CML-LBP, Short explained. The median age of the frontline cohort was 62 years [range, 34-83]. Among the 10 patients with relapsed/refractory Ph-positive ALL, 1 was primary refractory to [a] previous regimen, 4 were treated in first salvage, and 5 in second or later salvage. Among the 5 patients with CML-LBP, 3 had not received any prior therapy for blast phase disease, 1 was treated in first salvage, and 1 in second salvage.

Additional data indicated that the cohort of patients with CML-LBP had a CR or pathologic CR rate of 100%, as well as an MMR rate of 60%, and CMR rate of 40%. Moreover, the relapsed/refractory cohort achieved a rate of 88% in both MMR and CMR. In total, the overall patient population had a CR or pathologic CR rate of 96%, an MMR rate of 91%, and a CMR rate of 79%. No patients were reported to have an early death while on the study.

After the first cycle of treatment, the frontline ALL cohort had a CMR rate of 58%, an MMR rate of 26%, and 16% did not experience a response. Moreover, 75% of patients in the relapsed/refractory ALL cohort, and 20% in the CML-LBP cohort had a CMR after the first cycle, while 25% and 80% of patients from both cohorts did not respond, respectively.

Of the patients who experienced a CR or pathologic CR in the frontline ALL arm (n = 20), 1 died following CR due to post-procedural bleeding and hypovolemic shock, while 19 continue to experience ongoing responses without the need for stem cell transplantation. Notably, no patients in this have relapsed within 6 months.

In the relapsed/refractory ALL cohort, of the patients who responded (n = 9), 4 went on to receive HSCT, 1 of whom relapsed and died. Another patient relapsed and developed T315I and E255V mutations at relapse. Overall, 3 patients from this cohort are experiencing an ongoing response without the need for HSCT, while 1 patient died off study due to unknown causes.

In the CML-LBP arm, 2 responders (n = 5) relapsed, one of whom developed myeloid blast phase disease but is currently alive and in remission, while the other developed L248V and Y253H mutations at relapse but is currently alive and in remission following HSCT. Additionally, 3 patients continue to experience an ongoing response without HSCT.

After a median follow up of 12 months, the overall patient population is estimated to have 1- and 2-year EFS of 76% and 70%, respectively. Moreover, the estimated 1-year and 2-year OS were 93% and 80%, respectively. Notably, the relapsed/refractory AML cohort had an estimated 1- and 2-year EFS of 61% and 41%, respectively, as well as an estimated 1- and 2-year OS of 80% and 53%, respectively. Additionally, the CML-LBP arm had 60% estimated EFS rate at 1 and 2 years, respectively, as well as a 100% estimated 1- and 2-year rate.

Notably, there were no grade 4 or higher adverse effects (AEs) reported on the study. Common grade 3 AEs related to ponatinib in patients with ALL included elevated lipase (6%), alanine aminotransferase increase (ALT; 3%), cerebrovascular ischemia (3%), hypertension (3%) pancreatitis (3%), and deep vein thrombosis (3%). Grade 2 AEs included rash (11%), ALT increase (3%), and cerebrovascular ischemia (3%) and grade 1 AEs included rash (11%) and ALT increase (3%).

Although most AEs related to blinatumomab were grade 1 or 2 in patients with ALL, 1 patient developed grade 3 encephalopathy that was resolved by corticosteroids and treatment interruption, according to Short. Common grade 2 AEs included cytokine release syndrome (6%) and tremors (3%), as well as 1 patient who developed grade 1 tremors.

References

1. Short NJ, Kantarjian H, Konopleva MY, et al. Combination of ponatinib and blinatumomab in Philadelphia chromosome-positive acute lymphoblastic leukemia: Early results from a phase II study. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 7001.

2. Daver N, Thomas D, Ravandi F, et al. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2015;100(5):653-651. doi:10.3324/haematol.2014.118588

3. Ravandi F, OBrien S, Cortes J, et al. Long-term follow-up of phase II study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia-chromosome positive acute lymphoblastic leukemia. Cancer. 2015;121(23):4158-4164. doi:10.1002/cncr.29646

4. Rousselot P, Coud MM, Gokbuget N, et al. Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosomepositive ALL. Blood. 2016;126(6):774-782. doi:10.1182/blood-2016-02-700153

5. Jabbour E, Short NJ, Ravandi F, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study. Lancet Haematol. 2018;5(12):e618-e627. doi:10.1016/S2352-3026(18)30176-5

6. Martinelli G, Boissel N, Chevallier P, et al. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study. J Clin Oncol. 2017;35(16):1795-1802. doi:10.1200/JCO.2016.69.3531

7. Fo R, Bassan R, Vitale A, et al. Dasatinibblinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383:1613-1623. doi:10.1056/NEJMoa2016272

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HSCT-Sparing, Chemotherapy-Free Treatment of Ph+ ALL With Ponatinib/Blinatumomab Leads to 100% CR Rate - Cancer Network

Action Taken by Governor Phil Scott on Legislation – June 7, 2021 – Office of Governor Phil Scott

Montpelier, Vt. - Governor Phil Scott announced action on the following bills, passed by the General Assembly.

On June 7, Governor Scott signed bills of the following titles:

Governor Scott issued the following statement when signing S.3:

Public safety is a top priority for my Administration, as is the mental health of Vermonters. This important piece of legislation will help address the limitations of our current systems by lessening the gap between the criminal justice and mental health systems. It also takes steps to ensure due process in the criminal system, protect public safety, and ensure that those experiencing mental illness receive appropriate treatment. I want to thank our partners and members of the judiciary committees for their work.

Governor Scott issued the following statement when signing S.15:

Im signing this bill because I believe making sure voting is easy and accessible, and increasing voter participation, is important. Having said that, we should not limit this expansion of access to general elections alone, which already have the highest voter turnout.

For greater consistency and to expand access further, I am asking the General Assembly to extend the provisions of this bill to primary elections, local elections and school budget votes when they return to session in January.

Governor Scott issued the following statement when signing S.48:

Making it easier to live and work in Vermont to address our demographic and workforce crisis has been a top priority for my Administration. I am proud of the work we have done in previous years with the Secretary of States Office to make it easier for servicemen and women to transition into the civilian workforce in Vermont, and reforming rules to make it easier for people with licenses in other states to become licensed in Vermont.

After all weve been through the past 15 months, it is more clear than ever how important nurses are to our communities, and we need to continue to add tools to attract more to the Green Mountain State. Joining the compact will help us do that, while also ensuring more uniform standards and protecting public health.

To view a complete list of action on bills passed during the 2021 legislative session, click here.

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Action Taken by Governor Phil Scott on Legislation - June 7, 2021 - Office of Governor Phil Scott

Fate Therapeutics Highlights Positive Interim Data from its Phase 1 Study of FT516 in Combination with – GlobeNewswire

8 of 11 Patients in Dose Escalation Cohorts 2 and 3 Achieved Objective Response

6 of 11 Patients Achieved Complete Response, including 2 Patients Previously Treated with Autologous CD19 CAR T-cell Therapy

Favorable FT516 Safety Profile Was Observed; No FT516-related Serious Adverse Events or FT516-related Grade 3 or Greater Adverse Events

Outpatient Treatment Regimen Was Well-tolerated; No Events of Any Grade of Cytokine Release Syndrome, Immune Effector Cell-Associated Neurotoxicity Syndrome, or Graft-vs-Host Disease

SAN DIEGO, June 04, 2021 (GLOBE NEWSWIRE) -- Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer, today highlighted positive interim Phase 1 data from the Companys FT516 program for patients with relapsed / refractory B-cell lymphoma at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting being held virtually June 4-8, 2021. FT516 is the Companys universal, off-the-shelf natural killer (NK) cell product candidate derived from a clonal master induced pluripotent stem cell (iPSC) line engineered with a novel high-affinity, non-cleavable CD16 (hnCD16) Fc receptor, which is designed to maximize antibody-dependent cellular cytotoxicity (ADCC), a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells. The ongoing Phase 1 dose-escalation study of FT516 is currently enrolling patients in the fourth dose cohort of 900 million cells per dose.

As of the data cutoff date of March 11, 2021, four patients in the second dose cohort of 90 million cells per dose and seven patients in the third dose cohort of 300 million cells per dose were evaluable for assessment of safety and efficacy. Eight of eleven patients achieved an objective response, including six patients who achieved a complete response, as assessed by PET-CT scan per Lugano 2014 criteria (see Table 1). Patients had received a median of three prior lines of therapy and a median of two prior lines containing CD20-targeted therapy. Of the eleven patients, eight patients had aggressive B-cell lymphoma, five patients were refractory to their most recent prior therapy, and four patients were previously treated with autologous CD19 CAR-T cell therapy.

These additional data from our Phase 1 study of FT516 administered off-the-shelf in the outpatient setting continue to reinforce its differentiated safety profile and underscore its potential clinical benefit, said Wayne Chu, M.D., Senior Vice President of Clinical Development of Fate Therapeutics. Based on the favorable therapeutic profile of FT516 that continues to emerge and the potential to treat patients on-demand without delay, we plan to initiate multiple indication-specific, dose-expansion cohorts for patients with B-cell lymphomas to broadly assess FT516 in combination with CD20-targeted monoclonal antibody regimens, including those used as standard-of-care in earlier-line settings.

The ongoing Phase 1 clinical trial in relapsed / refractory B-cell lymphoma is assessing FT516 in an off-the-shelf treatment regimen of up to two cycles, with each cycle consisting of three days of conditioning chemotherapy (500 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine), a single-dose of rituximab (375 mg/m2), and three weekly doses of FT516 each with IL-2 cytokine support. The FT516 treatment regimen is designed to be administered in the outpatient setting.

Safety Data No dose-limiting toxicities, and no FT516-related serious adverse events or FT516-related Grade 3 or greater adverse events, were observed. The FT516 treatment regimen was well tolerated, and no treatment-emergent adverse events (TEAEs) of any grade of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease were reported by investigators (see Table 2). All Grade 3 or greater TEAEs were consistent with lympho-conditioning chemotherapy and underlying disease. Of note, a Grade 3 or greater TEAE of infection was reported in one patient only. There were no discontinuations due to adverse events, and no patients withdrew from the study except in the setting of disease progression. In addition, no evidence of anti-product T- or B-cell mediated host-versus-product alloreactivity was detected, supporting the potential to safely administer up to six doses of FT516 in the outpatient setting without the need for patient matching.

Activity Data As of the data cutoff date of March 11, 2021, eleven relapsed / refractory patients in the second and third dose cohorts were evaluable for assessment of safety and efficacy. Of the eleven patients, nine patients completed both FT516 treatment cycles and eight patients achieved an objective response, including six patients who achieved a complete response, as assessed by PET-CT scan per Lugano 2014 criteria. Notably, two of four patients previously treated with autologous CD19 CAR-T cell therapy achieved a complete response. Two patients showed progressive disease following the first FT516 treatment cycle and discontinued treatment. The Company previously reported that two patients treated in the first dose cohort (30 million cells per dose) showed progressive disease.

Patient Case Study The ASCO presentation featured a case study of a 36-year old male with triple-hit, high-grade B-cell lymphoma with rearrangements of MYC, BCL2, and BCL6 genes. The patient was refractory to all prior lines of therapy with the exception of autologous CD19 CAR T-cell therapy, for which a complete response of two months duration was achieved. The patient was most recently refractory to an investigational CD20-targeted T-cell engager and presented with bulky lymphadenopathy with the largest lesion measuring approximately 10 centimeters. The first FT516 treatment cycle resulted in a complete response with resolution of all metabolically active disease and 85% reduction in the size of target lesions. Subsequent to the data cutoff date of March 11, 2021, the patient completed a second FT516 treatment cycle after which the response assessment continued to show complete response.

As of March 11, 2021 database entry. Data subject to source document verification. CR = Complete Response; PR = Partial Response; PD = Progressive Disease CAR = Chimeric antigen receptor; DH/DE = Double-hit / double expressor; DLBCL = Diffuse large B-cell lymphoma; FL = Follicular lymphoma; Gr = Grade; HGBCL = High-grade B-cell lymphoma; iNHL = Indolent non-Hodgkin lymphoma; TH = Triple-hit; Transformed iNHL = Aggressive B-cell lymphoma transformed from indolent non-Hodgkin lymphoma 1 Cycle 2 Day 29 protocol-defined response assessment per Lugano 2014 criteria 2 Subject did not proceed to Cycle 2 3 Confirmed DLBCL (transformation from Gr3A FL) subsequent to the data cutoff date of March 11, 2021 4 Cycle 2 Day 29 protocol-defined response assessment reported subsequent to the data cutoff date of March 11, 2021

CRS = Cytokine Release Syndrome; DL = Dose Level; GvHD = Graft vs. Host Disease; ICANS = Immune Cell-Associated Neurotoxicity Syndrome; M = Million; SAE = Serious Adverse Event; TEAE = Treatment-Emergent Adverse Event 1 Includes two subjects in the first dose cohort of 30 million cells per dose

About Fate Therapeutics iPSC Product Platform The Companys proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that are designed to be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Companys first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Companys platform is uniquely designed to overcome numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics iPSC product platform is supported by an intellectual property portfolio of over 350 issued patents and 150 pending patent applications.

About FT516 FT516 is an investigational, universal, off-the-shelf natural killer (NK) cell cancer immunotherapy derived from a clonal master induced pluripotent stem cell (iPSC) line engineered to express a novel high-affinity 158V, non-cleavable CD16 (hnCD16) Fc receptor, which has been modified to prevent its down-regulation and to enhance its binding to tumor-targeting antibodies. CD16 mediates antibody-dependent cellular cytotoxicity (ADCC), a potent anti-tumor mechanism by which NK cells recognize, bind and kill antibody-coated cancer cells. ADCC is dependent on NK cells maintaining stable and effective expression of CD16, which has been shown to undergo considerable down-regulation in cancer patients. In addition, CD16 occurs in two variants, 158V or 158F, that elicit high or low binding affinity, respectively, to the Fc domain of IgG1 antibodies. Scientists from the Company have shown in a peer-reviewed publication (Blood. 2020;135(6):399-410) that hnCD16 iPSC-derived NK cells, compared to peripheral blood NK cells, elicit a more durable anti-tumor response and extend survival in combination with anti-CD20 monoclonal antibodies in an in vivo xenograft mouse model of human lymphoma. Numerous clinical studies with FDA-approved tumor-targeting antibodies, including rituximab, trastuzumab and cetuximab, have demonstrated that patients homozygous for the 158V variant, which is present in only about 15% of patients, have improved clinical outcomes. FT516 is being investigated in a multi-dose Phase 1 clinical trial as a monotherapy for the treatment of acute myeloid leukemia and in combination with CD20-targeted monoclonal antibodies for the treatment of advanced B-cell lymphoma (NCT04023071). Additionally, FT516 is being investigated in a multi-dose Phase 1 clinical trial in combination with avelumab for the treatment of advanced solid tumor resistant to anti-PDL1 checkpoint inhibitor therapy (NCT04551885).

About Fate Therapeutics, Inc. Fate Therapeutics is a clinical-stage biopharmaceutical company dedicated to the development of first-in-class cellular immunotherapies for patients with cancer. The Company has established a leadership position in the clinical development and manufacture of universal, off-the-shelf cell products using its proprietary induced pluripotent stem cell (iPSC) product platform. The Companys immuno-oncology pipeline includes off-the-shelf, iPSC-derived natural killer (NK) cell and T-cell product candidates, which are designed to synergize with well-established cancer therapies, including immune checkpoint inhibitors and monoclonal antibodies, and to target tumor-associated antigens using chimeric antigen receptors (CARs). Fate Therapeutics is headquartered in San Diego, CA. For more information, please visit http://www.fatetherapeutics.com.

Forward-Looking Statements This release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 including statements regarding the safety and therapeutic potential of the Companys iPSC-derived NK cell product candidates, including FT516, its ongoing and planned clinical studies, and the expected clinical development plans for FT516. These and any other forward-looking statements in this release are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that results observed in studies of its product candidates, including preclinical studies and clinical trials of any of its product candidates, will not be observed in ongoing or future studies involving these product candidates, the risk that the Company may cease or delay clinical development of any of its product candidates for a variety of reasons (including requirements that may be imposed by regulatory authorities on the initiation or conduct of clinical trials, the amount and type of data to be generated, or otherwise to support regulatory approval, difficulties or delays in subject enrollment and continuation in current and planned clinical trials, difficulties in manufacturing or supplying the Companys product candidates for clinical testing, and any adverse events or other negative results that may be observed during preclinical or clinical development), and the risk that its product candidates may not produce therapeutic benefits or may cause other unanticipated adverse effects. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Companys actual results to differ from those contained in the forward-looking statements, see the risks and uncertainties detailed in the Companys periodic filings with the Securities and Exchange Commission, including but not limited to the Companys most recently filed periodic report, and from time to time in the Companys press releases and other investor communications.Fate Therapeutics is providing the information in this release as of this date and does not undertake any obligation to update any forward-looking statements contained in this release as a result of new information, future events or otherwise.

Contact: Christina Tartaglia Stern Investor Relations, Inc. 212.362.1200 christina@sternir.com

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Fate Therapeutics Highlights Positive Interim Data from its Phase 1 Study of FT516 in Combination with - GlobeNewswire

Cancer research: New advances and innovations – Medical News Today

In the second part of our whats exciting the experts series, Medical News Today spoke with another group of cancer experts. We asked them what recent advances have given them the most hope. Here, we provide a sneak peek at the fascinating forefront of cancer research in 2021.

Cancer is not a single disease but a collection of diseases. It is complex and does not readily give up its secrets. Despite the challenges cancer poses, scientists and clinicians continue to hone the way in which they diagnose and treat it.

Modern medicine means that diagnosis rates for many cancers are up, as are survival rates. However, with an estimated 19.3 million new cases of cancer worldwide in 2020, there is still much work to be done.

MNT recently contacted a number of medical experts and researchers and asked them to speak about the aspects of cancer research that they find most exciting. Their answers are fascinating and demonstrate the incredible variety of approaches that scientists are using to understand and combat cancer.

We will start todays journey into cutting edge oncology with a surprising guest: magnetically responsive bacteria.

Due to the difficulty of targeting systemically delivered therapeutics for cancer, interest has grown in exploiting biological agents to enhance tumor accumulation, explained Prof. Simone Schrle-Finke, Ph.D., from ETH Zurich in Switzerland.

In other words, getting cancer drugs to the right place is not as straightforward as one might hope. Prof. Schrle-Finke is among the researchers who are now enlisting the help of specialized bacteria.

She told MNT how scientists have known for a century that certain bacteria can colonize tumors and trigger regression. She explained that today, thanks to modern genetic engineering techniques, attenuated bacteria are available that can have a therapeutic effect exactly where this is necessary.

These therapeutic effects include secretion of toxins, competition for nutrients, and modulation of immune responses.

However, despite the promise of bacterial cancer therapy, there are still challenges to meet. Delivering the doses to the right place and getting them into the tumor remain foremost among challenges hampering clinical translation only about 1% of a systemically injected dose reaches the tumor, explained Prof. Schrle-Finke.

To address these challenges, her team at ETH Zurich is using magnetically responsive bacteria.

These so-called magnetotactic bacteria naturally orient themselves like compass needles to Earths magnetic field.

Although this ability evolved for navigation, scientists are keen to find out whether magnetic steering or pulling could allow them to repurpose it for cancer delivery.

In a recent study, Prof. Schrle-Finke and her colleagues used rotating magnetic fields to override the bacterias natural propulsion. As the authors of the study explain, they used swarms of magnetotactic bacteria to create a directable living ferrofluid.

These magnetotactic bacteria have a high demand for iron, so once they reach the tumor, as Prof. Schrle-Finke told MNT, they can metabolically influence cancer cells through starvation from this vital nutrient. We have shown in in vitro models that an increasing number of bacteria induce an upregulation of iron-scavenging receptors and death in cancer cells.

By uniting engineering principles and synthetic biology, we aim to provide a new framework for bacterial cancer therapy that addresses a major remaining hurdle by improving the efficiency of bacterial delivery using safe and scalable magnetic stimuli to these promising living therapeutic platforms.

Prof. Simone Schrle-Finke, Ph.D.

Personalized medicine is transforming the landscape of medicine and how healthcare providers can offer and plan personalized care for each of their patients, believes Dr. Santosh Kesari, Ph.D., director of neuro-oncology at Providence Saint Johns Health Center in Santa Monica, CA.

Dr. Kesari is also chair of the Department of Translational Neurosciences at Saint Johns Cancer Institute and regional medical director for the Research Clinical Institute of Providence Southern California.

Describing personalized medicine, Dr. Kesari said, It is an approach for disease prevention and treatment that takes into account biological, genetic, behavioral, environmental, and social risk factors that are unique to every individual.

He continued, Personalized medicine is rooted in early detection and prevention; integrating data from genomics and other advanced technologies; digital health monitoring; and incorporating the latest medical innovations for optimizing outcomes.

This is becoming very apparent in oncology, where genetic testing for tumor mutations and predispositions is increasingly being utilized and showing more value in using targeted drugs more wisely and improving outcomes.

Dr. Santosh Kesari, Ph.D.

Some personalized cancer approaches are already in use, such as EGFR, HER2, and NTRK inhibitors and the super personalized CAR-T cells.

According to Dr. Kesari, the future of personalization is bright, and progress has only accelerated in the past 5 years.

Continuing with the personalization theme, Dr. Robert Dallmann from Warwick Medical School at Warwick University in the United Kingdom talked with us about chronotherapy:

Propelled by the 2017 Nobel Prize in Medicine or Physiology [going] to three circadian biologists for uncovering the molecular mechanism of circadian biological clocks, cancer chronotherapy is gaining critical momentum to enter mainstream oncology especially in the context of personalized medicine.

Dr. Dallmann explained that many key physiological processes in the cells of our body are modulated in a daily fashion by the circadian clock. These cellular clocks are disrupted in some tumors but not in others.

Interestingly, a functional clock in the tumor predicts the survival time of patients, which has been shown for brain as well as breast tumors.

Therefore, he explained, if scientists could determine the clock status in solid tumors, it would allow doctors to more easily determine whether a patient is at high or low risk. It might also help guide therapy.

There is great potential in optimizing treatment plans with existing drugs by taking into account the interaction with the circadian system of the patient, continued Dr. Dallmann.

More recently, the circadian clock mechanism itself has been proposed as a novel treatment target in glioblastoma. The authors of the glioblastoma study concluded that pharmacologic targeting of circadian networks specifically disrupted cancer stem cell growth and self-renewal.

However, whether this might be generalized to many solid tumors or even other chronic diseases remains to be elucidated, said Dr. Dallmann.

In summary, he told MNT, circadian clocks have long been recognized to modulate chronic disease on many levels. The increased mechanistic understanding has the potential to improve diagnosis and existing treatments of cancer, as well as develop a new class of clock-targeting treatments.

Dr. Chung-Han Lee is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York. He is also a member of the Kidney Cancer Associations Medical Steering Committee. He talked us through recent advances in the treatment of kidney cancer.

The development and subsequent regulatory approval of combination immunotherapy for patients with metastatic kidney cancer have led to transformative change in the lives of many patients and are the hallmark of how greater scientific understanding has impacted cancer care, Dr. Lee told MNT.

Prior to 2005, treatment for metastatic kidney cancer was very limited, with most patients passing away in less than 1 year despite undergoing treatment. According to Dr. Lee, the development of antiangiogenic drugs that inhibit the growth of new blood vessels was among the first breakthroughs to improve the outcomes for patients.

However, even with antiangiogenic drugs, most patients ultimately developed resistance to treatment, and 18 months was considered a long-term response. Next came immunotherapies.

Prior to the development of antiangiogenic medications, it was known that kidney cancer could be treated by activating the immune system to better recognize the disease. However, the tools to activate the immune system were often very nonspecific. Therefore, responses to these early immunotherapies were rare, and the side effects related to treatment were not only burdensome but also could be life threatening.

With recent advances in immunotherapy, we have demonstrated that more targeted immunotherapies that activate specific immune checkpoints are not only possible but can have substantially increased activity against disease.

Two emerging treatment approaches have now become the new standard of care for kidney cancer: dual immunotherapies (such as ipilimumab/nivolumab) or combinations of antiangiogenic targeted therapies with immunotherapies (such as axitinib/pembrolizumab).

In patients treated with ipilimumab and nivolumab, over 50% remain alive at 4 years, and with some [combined antiangiogenic and immunotherapy approaches], nearly 50% of patients remain on their initial therapy at 2 years.

Despite these advances, Dr. Lee is far from complacent, telling us that there remains considerable work to be done. [] Unfortunately, in 2021, for most patients, kidney cancer remains fatal. Even for those who have outstanding responses to treatment, most still require ongoing systemic therapy.

With the rapid improvements in treatments, the development of correlative biomarkers, and the improved biologic understanding of the disease, we have only started to entertain the possibility of curative, time-limited therapy.

Building on the sacrifices of patients and caregivers and the hard work of clinicians, research staff, and scientists, a cure may, one day, be a reality for our patients, he concluded.

Our study from late 2020 has shown that the antidepressant sertraline helps to inhibit the growth of cancer cells in mice, Prof. Kim De Keersmaecker from KU LEUVEN in Belgium told MNT.

Other studies had already indicated that the commonly used antidepressant has anticancer activity, but there was no explanation for the cause of this. Weve been able to demonstrate that sertraline inhibits the production of serine and glycine, causing decreased growth of cancer cells.

Cancer cells and healthy cells are often reliant on the amino acids serine and glycine, which they extract from their environment. However, certain cancer cells produce serine and glycine within the cell. They can become addicted to this production.

This internal production of serine and glycine requires certain enzymes, and these enzymes have become targets for cancer researchers. Preventing them from functioning can starve the cancer cells.

Previous studies have identified inhibitors of serine/glycine synthesis enzymes, but none have reached the clinical trial stage. As the authors of a KU LEUVEN study note, because sertraline is a clinically used drug that can safely be used in humans, it might make a good candidate.

Prof. De Keersmaecker explained that when used with other therapeutics, the drug strongly inhibited the growth of cancer cells in the mice.

The authors of the study concluded: Collectively, this work provides a novel and cost efficient treatment option for the rapidly growing list of serine/glycine synthesis-addicted cancers.

Christy Maksoudian from the NanoHealth & Optical Imaging Group team at KE LEUVEN is excited about the promise of nanotechnology for the treatment of cancer. She told MNT that because of the unique properties that emerge at such a small scale, nanoparticles can be designed in a multitude of ways to exhibit specific behaviors in organisms.

Currently, she explained, many available nanoformulations in the clinic are composed of organic materials because of their biocompatibility and safety. In this context, organic refers to compounds that include carbon.

However, she explains that inorganic nanomaterials, which do not contain carbon, also hold promise for cancer treatment because they possess further functionalities.

For instance, some magnetic nanoparticles, such as those of superparamagnetic iron oxide, can be magnetically guided toward the tumor, while gold nanoparticles generate heat upon exposure to near-infrared light and can, therefore, be used for photothermal therapy (via tumor tissue ablation).

In short, it is possible to introduce gold nanoparticles to the bloodstream of people with cancer. From there, these nanoparticles accumulate in tumors because tumors have particularly leaky blood vessels. Once that region is exposed to near-infrared light, the gold nanoparticles heat up and, consequently, kill cancer cells.

Because of the potential of such broad range of nanomaterial designs, there are always novel cancer therapies being developed.

Christy Maksoudian

I am excited to take part in this movement with my work on copper oxide nanoparticles. Maksoudian and her colleagues use copper oxide nanoparticles doped with 6% iron.

Maksoudian told MNT that these nanoparticles exploit intrinsic metabolic differences between cancer cells and healthy cells to induce high levels of toxicity in cancer cells while only causing reversible damage in healthy tissue.

The fact that such cancer-selective properties can arise due to minor modifications of the nanoparticles at the nanoscale is truly extraordinary and reaffirms the significant role that nanomedicine can play in expanding the treatment landscape for oncology.

Cancer is complex, so approaches to its treatment must match that complexity. As the summaries above demonstrate, scientists are not short on ingenuity, and the battle against cancer continues at pace.

Read the first part of our series on cancer researchers and their exciting work here.

Excerpt from:
Cancer research: New advances and innovations - Medical News Today

Naturally Treat & Heal The Cause of Pain with Regenerative Therapies – The Mountaineer

By Dr. John C. Haasis III, M.D

Daisy Stem Cell Therapy

Your body is an amazing feat of engineering. Many complex physical, chemical, and neurological processes all work together to make you who you are. Too much medicine today focuses on treating a symptom rather than solving a problem. Regenerative therapies are a spectrum of cutting edge therapeutic techniques used to naturally treat and heal the cause of a painful condition rather than masking the symptom. Therapies such as the ones listed below stimulate and accelerate your own bodys natural ability to heal itself.

Stem Cells

Stem cells are undifferentiated cells, which allow them to develop into another type of cell that is required to repair or replace damaged tissue. Stem cell therapy can repair tissues that are too damaged to heal on their own. Stem cells can stimulate the formation of cartilage, tendon, ligaments, bone and fibrous connective tissues.

Allograft Tissues

A purified amniotic source that contains a healing matrix of cytokines, growth factors, and proteins that helps to rejuvenate and heal damaged tissue can be used via injection.

Exosomes

Exosomes are extracellular vesicles which can be used alone or in combination with stem cell therapy to speed up healing. Exosome therapy can be injected into the affected area for orthopedic injuries, used in aesthetic procedures for cosmetic enhancement or given intravenously for anti-aging.

Platelets

Platelet rich plasm (PRP) therapy utilizes platelets taken from the patients own blood to rebuild damaged tendons and cartilage. Platelets normally circulated within the blood stream and are responsible for blood clotting and initiating a healing response in an acute injury. Many acute injuries do not heal adequately and can lead to chronic pain and loss of function of the injured area. Platelet rich plasma (PRP) therapy allows us to harvest the patients own platelets and re-inject those platelets into sites of injury to initiate healing and improvement of function.

Technology

All procedures are performed under the guidance of ultrasound or a fluoroscopy unit to maximize results. We have incorporated the latest innovations in equipment, supplies, and protocols to optimize outcomes. In addition, we have partnered with leaders in the field, with proven track records, to provide the very best stem therapy products to our patients.

Dr. John C. Haasis III, M.D., is Medical Director and Founder of Daisy Stem Cell Therapy and Advanced Regenerative Medicine Centers of the Carolinas. With over 25 years of comprehensive and interventional pain management experience, Dr. Haasis has treated thousands of patients in our region.

Dr. Haasis received his undergraduate degree in Biology from Pennsylvania State University was accepted into a Ph.D. program at Temple University where he studied molecular biology. He received his medical degree from the Medical College of Pennsylvania in 1992, followed by Anesthesia and Pain management training at Duke University Medical Center. He currently enjoys a thriving practice with six office locations in NC and SC. Over the years, he and his staff have made it their mission to help people manage their pain and improve function so that they can enjoy life again.

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Rinri Therapeutics Secures Innovate UK Funding Grant for 3.2m Project to Advance its Novel Cell-Based Therapy to Restore Hearing Loss – PRNewswire

SHEFFIELD, England, May 13, 2021 /PRNewswire/ -- Rinri Therapeutics ('Rinri'), a biotechnology company developing a novel cell-based therapy to restore hearing loss, is delighted to announce that it has secured, a grant from Innovate UK, the UK's innovation agency. This grant will fund a 3.2 million project to further develop Rinri's novel stem cell therapy to reverse sensorineural hearing loss (SNHL) an area / a condition where there remains a significant global unmet need.

The project will be led by Rinri in collaboration with the Cell and Gene Therapy Catapult (CGTC), and the Universities of Sheffield and Nottingham.

Over the course of the project, the CGTC will help establish a process and analytical tools for clinical trial manufacture of Rinri's stem cell therapy for hearing loss, Sheffield University will further the nonclinical data package and Nottingham University will develop the necessary techniques for the first in human trial of Rinri's cell-based therapy to restore hearing loss.

Rinri's underlying technology, based on innovative stem cell research originating from the University of Sheffield, seeks to reverse SNHL by repairing the damaged cytoarchitecture in the inner ear. SNHL happens when there is damage to the hair cells in the cochlear and/or the auditory nerve. There are currently no pharmacological treatments available for SNHL despite the rapid increase in the number of patients that suffer from this condition globally.

Dr Simon Chandler, CEO of Rinri Therapeutics, commented: "We are delighted to receive this substantial grant from Innovate UK to conduct further important research into our stem cell therapy for hearing loss. We have made superb progress in refining and optimising our technology following our ground-breaking proof of concept data. This grant will be instrumental in supporting the development and initiating clinical studiesof our pioneering approach to reverse hearing loss."

Matthew Durdy, CEO of the Cell and Gene Therapy Catapult added: "Rinri's cutting-edge stem cell therapy is a very exciting development in the field, and we look forward to working with them to prepare for clinical manufacture. Combining forces under this Innovate UK funded grant will help accelerate the development of this promising technology."

Andrew Hogben, Head of Impact and Intellectual Property at the University of Sheffieldsaid: "Given Rinri was founded on pioneering research led by Professor Marcelo Rivolta at the University of Sheffield, we are really excited to participate in Rinri's Innovate UK funded project alongside Cell and Gene Therapy Catapult and Nottingham University to advance this novel treatment into the clinic."

Professor Douglas Hartley, from the School of Medicine at the University of Nottingham, said: "This significant award from Innovate UK is a substantial boost to our pioneering UK partnership that could lead to a revolution in the treatment of disabling hearing loss."

About Rinri Therapeutics

Rinri Therapeutics is a private biotechnology company developing advanced stem cell-based therapeutics to restore hearing. The company's pioneering technology seeks to reverse sensorineural hearing loss (SNHL) through the repair of the damaged cytoarchitecture in the inner ear. SNHL is estimated to affect 64 million patients in the US and 34 million in Europe. There are currently no pharmacological treatment options for SNHL patients.

Rinri, is backed by Boehringer Ingelheim Venture Fund (BIVF), UCB Ventures, BioCity, the University of Sheffield and the UK Future Fund. Rinri was founded in late-2018 and is headquartered in Sheffield, UK.

For more information, please visit: http://www.rinri-therapeutics.com

Contacts:

Rinri Therapeutics Dr Simon Chandler, CEO [emailprotected]

Citigate Dewe Rogerson Sylvie Berrebi, Frazer Hall E: [emailprotected] T: +44 (0)20 7638 9571

About Cell and Gene Therapy CatapultThe Cell and Gene Therapy Catapult was established as an independent centre of excellence to advance the growth of the UK cell and gene therapy industry, by bridging the gap between scientific research and full-scale commercialisation. With more than 330 employees focusing on cell and gene therapy technologies, it works with partners in academia and industry to ensure these life-changing therapies can be developed for use in health services throughout the world. It offers leading-edge capability, technology and innovation to enable companies to take products into clinical trials and provide clinical, process development, manufacturing, regulatory, health economics and market access expertise. Its aim is to make the UK the most compelling and logical choice for UK and international partners to develop and commercialise these advanced therapies. The Cell and Gene Therapy Catapult works with Innovate UK. For more information please visit ct.catapult.org.uk or visit http://www.gov.uk/innovate-uk.

For further information please contact

FTI Consulting for the CGT Catapult:

Michael Trace +44 (0) 203 319 5674 / [emailprotected]

George Kendrick +44 (0) 203 727 1411/ [emailprotected]

About The University of Sheffield With almost 29,000 of the brightest students from over 140 countries, learning along-side over 1,200 of the best academics from across the globe, the University of Shef-field is one of the world's leading universities. A member of the UK's prestigious Russell Group of leading research-led institutions, Sheffield offers world-class teach-ing and research excellence across a wide range of disciplines. Unified by the power of discovery and understanding, staff and students at the university are committed to finding new ways to transform the world we live in. Sheffield has six Nobel Prize win-ners among former staff and students and its alumni go on to hold positions of great responsibility and influence all over the world, making significant contributions in their chosen fields.

About The University of Nottingham The University of Nottingham is a research-intensive university with a proud heritage, consistently ranked among the world's top 100. We have a pioneering spirit, expressed in the vision of our founder Sir Jesse Boot, which has seen us lead the way in establishing campuses in China and Malaysia - part of a globally connected network of education, research and industrial engagement. We are ranked eighth for research power in the UK according to REF 2014. We have six beacons of research excellence helping to transform lives and change the world; we are also a major employer and industry partner - locally and globally. Alongside Nottingham Trent University, we lead the Universities for Nottingham initiative, a pioneering collaboration which brings together the combined strength and civic missions of Nottingham's two world-class universities and is working with local communities and partners to aid recovery and renewal following the COVID-19 pandemic.

SOURCE Rinri Therapeutics

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CAR T-Cell Therapy UCARTCS1A Shows Early Activity in Relapsed/Refractory Myeloma – OncLive

Expansion and persistence of UCARTCS1A was observed and was found to correlate with clinically meaningful antimyeloma activity and serum cytokine changes in very heavily pretreated patients with multiple myeloma. Also, the CAR T-cell product was noted to be detectable in patients, regardless of donor and batch.

These preliminary data validate CS1 as a target for CAR T-cell products in multiple myeloma and that UCARTCS1A is a promising potential therapy for [those with this disease], Krina K. Patel, MD, MSc, an associate professor of the Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said during a presentation on the results.

One of the benefits that comes with utilizing an allogeneic CAR T-cell approach over an autologous approach is that it affords the opportunity for off-the-shelf product availability, according to Patel. Patients are able to avoid a prolonged wait for the CAR T cells to be manufactured; the cells are able to be administered within a couple of weeks, Patel explained. In contrast, it can take 4 to 5 weeks to bring an autologous product to a treatment center.

Scalable manufacturing is another benefit of allogeneic approaches, and this can reduce costs and yield 100 or more doses from 1 batch of donor cells. Also, for allogeneic approaches, T cells are collected from healthy donors; these patients have not been given many steroids, chemotherapy, or have undergone autologous transplant. As such, their T cells will likely be more potent, Patel explained. Lastly, more flexible dosing is an option with allogeneic approaches; this allows for the possibility of redosing and alternate schedules.

UCARTCS1A is the first allogeneic CAR T-cell product developed to target CS1 and SLAMF7, both of which are highly and consistently expressed in multiple myeloma, according to Patel. The product knocks out the TRAC gene to avoid graft-versus-host disease through disruption of T-cell receptor (TCR) assembly. The product also knocks out CS1 to facilitate robust expansion and yield, while avoiding fratricide. Lastly, UCARTCS1A has a RQR8 safety switch, which is a CD20 mimotope that can use rituximab (Rituxan) to kill the cells, if necessary.

Previously, the CAR T-cell product demonstrated durable in vivo efficacy against MM1S tumors. Here, NSG mice were given a 5 x 105 MM1S myeloma cell line, which is known to be pretty aggressive, Patel noted; this was labeled with GFP and was given for 10 days. Subsequently, the mice received the CAR T cells. Investigators observed CAR-positive cells at day 4 and M protein, which is a surrogate marker for multiple myeloma in mice and patients.

We were able to see an early response, as well. However, eventually, the T cells went down, and the myeloma started to go back up, Patel added. Looking at the imaging, mice who [received] CAR T cells obviously did much better and lived longer and there was a dose-dependent response where the mice that got the higher dose did better, with a much longer survival. Investigators were also able to demonstrate that the mice that received the CAR T-cell therapy experienced improvement in lytic lesions over time.

MELANI-01 enrolled patients with confirmed multiple myeloma per International Myeloma Working Group criteria who relapsed following previous therapy for their disease. To be eligible for enrollment, patients needed to have an ECOG performance status of 0 to 2 and acceptable organ function. They could have not previously received an investigational drug or cell/gene therapy targeting CS1.

The key eligibility [for this trial] is similar to most cell therapy trials [that are done in] myeloma. However, for most of those trials, patients are not able to have previously received CAR T cells or BCMA-directed therapies, Patel said. In this trial, [those are not] ineligibility [criteria]. Our patients had really relapsed/refractory [disease.]

After going through screening, patients received lymphodepletion chemotherapy that was comprised of fludarabine at a daily dose of 30 mg/m2 for 3 days followed by cyclophosphamide at a daily dose of 1 g/m2, also for 3 days. The [cyclophosphamide] dose was 2 to 3 times higher than what [has been] used in most other trials, Patel noted.

Patients then received treatment with UCARTCS1A. Patients were started at dose level 1, where they received 1 x 106/kg. One patient went on to dose level 2, which was 3 x 106/kg. Patients underwent their first disease evaluation at day 28.

The primary and secondary objectives of the study included safety and tolerability of UCARTCS1A, as well as determining the maximum-tolerated dose and efficacy of the product. Exploratory end points are examining expression of CS1 on multiple myeloma cells, UCARTCS1A expansion and persistence, and changes in serum biomarkers or immune cell reconstitution.

Patel shared information on 5 patients who received treatment with UCARTCS1A to date; 4 of the patients received dose level 1 (102-101, 102-109, 102-107, and 102-111) and 1 patient (102-113) received dose level 2.

Four of the 5 patients (102-101, 102-109, 102-107, and 102-113) had previously received over 11 lines of therapy and had most had previously received a BCMA-directed therapy. Just to put this into context, most of the autologous CAR T-cell trials that are done have patients who had a median of 5 to 6 prior lines of treatment, Patel noted.

One patient (102-111) had received only 4 prior lines of therapy and was the only patient who had cells expand and responded on dose level 1. However, the patient had very high-risk disease with 90% plasma cells. He had the most myeloma going into the trial, Patel said.

Notably, patient 102-113 who had received dose level 2 and also experienced an expansion of cells at day 7 had received 13 prior lines of therapy, including 2 prior BCMA-targeted CAR T-cell therapies, the last of which was administered just 5 months prior to the study.

Patient 102-111 was 55 years of age, had 4 prior lines of therapy and 90% of bone marrow involvement. He had relapsed within 6 months of every prior line of therapy and he never experienced more than a partial response (PR) to any of his prior treatments, according to Patel. When looking at his peripheral blood at day 28, investigators noted that the CD45+ CAR-positive lymphocytes was almost 72% and a subgroup of CD8+ effector cells that are TCRnegative CAR-positive cells, were about 46%.

[Some might] think that allogenic cells would not last very long, but for this patient, we definitely saw the majority of T cells still there that were CAR positive, Patel said. For him, we were able to get a bone marrow [sample] at month 3, where we could also see CD45+ CAR-positive cells at 60% in the bone marrow of all CD45+ cells. The CD8+ effector [cells] were at 92%.

Moreover, CAR-positive cells were observed in the patients peripheral blood starting at day 14; they peaked at day 21, and then started to decrease. However, some of these cells were still observed at day 80 to 86, according to Patel. The patients white blood cell count was low, while peripheral blood was high, until approximately day 28, before it started decreasing. However, the patients bone marrow remained high, even at day 77, in terms of the vector copy number of the CAR T cells.

This patient experienced grade 2 cytokine release syndrome (CRS) within the first week of cell infusion. The patient also developed hemophagocytic lymphohistiocytosis (HLH), which has previously been observed with other autologous CAR T-cell products in multiple myeloma. Investigators treated the patients with anakinra (Kineret), dexamethasone, etoposide, and the rituximab kill switch. The rationale for triggering the kill switch was because the patient had reactivation of HHV6, which developed into HHV6 encephalitis.

Per the FDA, we were monitoring HHV6 and HHV7 levels, as we do for most of our CAR T-cell therapy trials. We were monitoring this [and when his levels were high enough that we decided to treat], the patient got admitted for antivirals, improved, went home, and then came back with an encephalitis picture. Initially, we treated him dexamethasone and gave the rituximab kill switch thinking that if it was immune effector cell-associated neurotoxicity, we could kill off some of the cells. But in the end, it was HHV6 encephalitis.

Although the patient did improve, and he had double antiviral coverage, he eventually passed away on day 109 from organizing pneumonia in the context of prolonged lymphopenia in the absence of multiple myeloma progression.

At the time, he did not have any myeloma and he had [experienced] this response that he had never had before, a near complete response Patel explained. We looked at his bone marrow, which was minimal residual diseasenegative at the 10-5 level. However, because of the prolonged lymphopenia, he ended up with this infection.

Multiple factors may have contributed to the prolonged lymphopenia, including viral reactivation, concomitant antivirals, and recent prior stem cell transplant, Patel explained.

The other patient with expansion, patient 102-113, was observed to have 25% CD45+ CAR-positive lymphocytes in the peripheral blood at day 9, 77% of which were CD8+ effector cells, according to Patel. Notably, investigators were unable to collect a bone marrow sample from the patient. In the peripheral blood, investigators observed expansion at day 7 and then a peak, and then the vector copy number persisted over the time the blood samples were obtained.

This patient had previously received 14 lines of therapy, including 2 previous BCMA-directed CAR T-cell therapies and associated lymphodepleting regimens, autologous transplant, and venetoclax (Venclexta), as his last line of therapy. The patient did not have any options left and we saw this fantastic response, where the lambda light chains had gone done by almost 90%; his M protein had at least a PR by just day 14.

However, this patient had CRS and HLH, as well. We treated him with etoposide, anakinra, dexamethasone, and the rituximab kill switch and he had improvement in his platelet and his liver function tests, Patel added. The HLH clinically improved for him. However, at day 25, he passed away.

An autopsy revealed G5 hemorrhagic pancreatitis, although he had not exhibited any clinical signs of this condition during his hospital stay. Investigators also found disseminated mucormycosis and pseudomonal pneumonia.

Select serum cytokine changes over time were found to correlate with expansion of the CAR T-cell product. Cytokines were increased much more in the patients who expanded vs those who did not expand at all, Patel noted.

MELANI-01 is currently enrolling patients with protocol modifications, including restarting at dose level -1 (3 x 105). Moreover, lower doses of lymphodepleting chemotherapy are being administered now in an attempt to address lymphopenia and lead to added expansion. The trial will also have additional requirements for monitoring and managing patients with regard to opportunistic infections, as well as CRS and HLH.

Patel KK, Bharathan M, Siegel D, et al. UCARTCS1A, an allogeneic CAR T-cell therapy targeting CS1 in patients with relapsed/refractory multiple myeloma (RRMM): preliminary translational results from a first-in-human phase I trial (MELANI-01). 2021 American Society of Gene and Cell Therapy Annual Meeting; May 11-14, 2021; Virtual. Accessed May 13, 2021. Abstract 118.

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CAR T-Cell Therapy UCARTCS1A Shows Early Activity in Relapsed/Refractory Myeloma - OncLive

With $52 Million Series A, Appia Bio Anticipates a Bright Future in Cell Therapy – BioSpace

Appia co-founder and chief executive officer, JJ Kang/Photo Courtesy of Appia Bio

Backed by $52 million in Series A financing led by 8VC and named after a feat of engineering in ancient Rome, Appia Bio jumped into the cell therapy fray this morning with a promising scalable technology platform.

The company is named after the Aqua Appia, which is the first Roman aqueduct. It was kind of a feat of engineering and it brought water to a lot more people, and that thematically connects well. We want to engineer these cells and provide a broader reach for cell therapy through allogeneic off-the-shelf, said Appia co-founder and chief executive officer, JJ Kang, Ph.D.

Appia is developing engineered allogeneic cell therapies from hematopoietic stem cells (HSCs) for cancer patients. Its ACUA platform utilizes the biology of lymphocyte development with CAR and TCR gene engineering to produce CAR-engineered invariant natural killer T (CAR-iNKT) cells from HSCs.

The Los Angeles-based biotech is spun out of the pioneering work ofLili Yang, Ph.D., an associate professor at the University of California, Los Angeles (UCLA).

In addition to the $52 million votes of confidence provided by 8VC, Two Sigma Ventures, and seed investors, Sherpa Healthcare Partners and Freeflow Ventures, Appias newly announced scientific board is packed to the brim with wisdom.

Appia is co-founded by Nobel laureate winner and former president of theCalifornia Institute of Technology, Dr. David Baltimore. Edmund Kim, Ph.D., former VP of corporate development atKite Pharma(Gilead Sciences), comes on board as chief operating officer, while Jeff Wiezorek, MD, former head of cell therapy development at Kite and a previous student of Baltimores, joins as chief medical officer.

One of those guys, Jeff, has been a post-doc with me, so hes well-trained, quipped Baltimore.

In an exploding and crowded field, how does Appia differentiate itself?

I think in being an off-the-shelf allogeneic cell, charged and ready to go, said Baltimore. The secret here is Lili Yang, who figured out how to grow very large numbers of iNKT cells from a single harvest of hematopoietic stem cells. So we can make large numbers of cells to treat many multiples of patients from a single donor source. And we can prepare that ahead of time. So that means that no matter what their own HLA [human leukocyte antigen] is, these cells can be used therapeutically.

AQUA is also able to leverage these iNKT cells in a scaleable manner.

The big step forward with this technology is that starting from these hematopoietic stem cells, we can drive to the these invariant NKT cells that are actually naturally quite rare. Through this platform, we can produce a lot of these cells and do so in a scaleable, fullyex vivomanner that gives us a path forward for industry use for commercialization, said Kang.

Appia is now ready to power its extensive research forward into the clinic.

We have space now and we have money, we have people, said Baltimore. Were in the process of the technology transfer. The second step is to show that it will work in animal systems. Lili has done that, but we want to be able to show that we can do that. Then is the big step: Preparing ourselves for initial clinical trials. That will be a little ways down the road, but with the investments that we have now, we should be in a position to carry that step through.

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With $52 Million Series A, Appia Bio Anticipates a Bright Future in Cell Therapy - BioSpace