HER2-Specific CAR T Cells Induce Early Efficacy Without Dose-Limiting Toxicities in Pediatric CNS Tumors – OncLive

The clinical evidence included high concentrations of C-X-C motif chemokine ligand 10 (CXCL10) and C-C motif chemokine ligand 2 (CCL2) in the cerebrospinal fluid (CSF) and serum samples.

This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients, Nicholas Alexander Vitanza, MD, an assistant professor at the Ben Towne Center for Childhood Cancer Research, and a staff member of the Cancer and Blood Disorders Center, Brain Tumor Program, Apheresis, at Seattle Childrens, and coauthors, wrote in the study publication.

Although the integration of CAR T-cell therapy has provided a novel therapeutic modality to manage multiple hematologic malignancies, the utility of CAR T cells is not fully understood for pediatric patients with CNS tumors.

HER2 offers a valid target for CAR T-cell therapy in CNS tumors because it is widely expressed on a significant proportion of biologically diverse CNS tumors such as ependymoma, glioblastoma, and medulloblastoma, as well as CNS cancer stem cells. Moreover, HER2 is not expressed on normal CNS tissue.

Monoclonal antibodies, such as trastuzumab (Herceptin), are beneficial for patients with some HER2-expressing cancers but have limited activity in CNS tumors that require a therapy that crosses the blood-brain barrier. CNS tumors also harbor less HER2 expression compared with malignancies like breast cancer.

As such, directly administering HER2-directed therapy to the tumor site could be a lucrative strategy for patients with CNS tumors.

Preclinical data demonstrated that spacer length was correlated with improved activity of HER2-specific CAR T cells. Based on this, the single-institution BrainChild-01 trial used a medium-length spacer HER2CAR to evaluate repeated locoregional delivery of HER2-specific CAR T cells for pediatric patients with recurrent or refractory CNS tumors.

Following CAR T-cell manufacturing, patients were treated in the outpatient setting for up to 6 courses. Course 1 consisted of 3 weeks of a 1 x 107 dose of CAR T cells (DL1), followed by clinical evaluation in week 4. Course 2 consisted of 1 week of DL1 treatment, 2 weeks of a 2.5 x 107 dose of CAR T cells (DL2), followed by clinical and radiographic evaluation in week 4. Courses 3 through 6 retained the same dosing schedule at the highest tolerated dosing levels, which included 2 additional tiers: 5 x 107 [DL3] and 10 x 107 [DL4].

The BrainChild-01 HER2CAR T-cell product was manufactured under a process designed to yield balanced numbers of CD4+ and CD8+ lentivirally transduced T cells exhibiting limited terminal differentiation with enrichment for the CAR+ population of cells mid-culture, Vitanza and coauthors wrote.

The initial 3 patients were required to be from 15 to 26 years old. This age group is more capable of self-reporting neurologic changes compared with a younger patient population, so they were specifically used for the initial evaluation.

The first eligible 3 patients underwent apheresis and had CAR T-cell products that were in-line with release criteria. As such, the patients were assigned to the appropriate treatment arms: repeated locoregional CNS infusion into the CNS tumor or tumor cavity (arm A; n = 1) vs repeated locoregional CNS infusion into the ventricular system (arm B; n = 2).

All patients had undergone at least 3 prior tumor-directed surgical procedures, at least 1 prior irradiation, and at least 1 prior chemotherapy regimen. Additionally, all patients had presumed pediatric biology of their tumors.

A 19-year-old female patient enrolled on arm A was diagnosed with WHO grade III localized anaplastic astrocytoma. She had 1.95 x 109 total nucleated cells manufactured and 1.87 x 109 EGFRt+ CAR T cells manufactured. She received 6 doses of treatment.

Both patients enrolled on arm B were males with WHO grade III metastatic ependymoma. The first, a 16-year-old, had 3.2 x 109 total nucleated cells manufactured, 2.97 x 109 EGFRt+ CAR T cells manufactured, and received 9 doses of treatment. The second patient, aged 26, had 2.06 x 109 total nucleated cells manufactured, 1.87 x 109 EGFRt+ CAR T cells manufactured, and received 9 doses of treatment. The latter patients product in arm B had initial failure of viability screening, but with 2 additional manufacturing attempts, enough CAR T cells were generated to complete a minimum of 2 treatment courses.

The study was designed to primarily assess feasibility, safety, and tolerability, with assessment of CAR T-cell distribution and disease response as secondary objectives.

Patients experienced post-treatment symptoms. One patient who underwent imaging experienced radiographic evidence of treatment-mediated localized CNS immune activation.

Additional results showed that the most common adverse effects (AEs) observed in all patients were headache, pain at metastatic sites of spinal cord disease, and transient worsening of a baseline neurologic deficit. Additionally, the 2 patients on arm B experienced fever within 24 hours following infusion. These AEs were deemed possibly, probably, or definitely related to CAR T-cell therapy.

Systemic C-reactive protein elevation was also noted in all patients and overlapped with the timing of headaches and/or pain.

Regarding CSF cytokines and radiographic imaging, CAR T cells were not detected in any patient at any time point following infusion in CSF via flow cytometry or in peripheral blood via quantitative polymerase chain reaction. NonCAR T cell populations of CD4+ and CD8+ T cells were detected in CSF after infusion.

Cytokines, including CXCL10, CCL2, granulocyte colonystimulating factor, granulocyte-macrophage colony-stimulating factor, IFN2, IL-10, IL12-p70, IL-15, IL1, IL-6, IL-7, and tumor necrosis factor, were detected in the CSF following infusion. One patient also had elevated VEGF.

Additional studies are planned to evaluate the relationship between target antigen density and clinical toxicity and response.

With these findings, the trial is planned to enroll the broader age cohort of patients aged 1 to 26 years. Notably, the trial will include patients with diffuse midline glioma.

Two additional studies are also planned. BrainChild-02 (NCT03638167) will deliver EGFR-specific CAR T cells to pediatric patients with recurrent or refractory EGFR-positive CNS tumors. BrainChild-03 (NCT04185038) will deliver B7-H3specific CAR T cells to pediatric patients with recurrent or refractory CNS tumors or diffuse intrinsic pontine glioma.

Gleaning the results of all 3 BrainChild studies, the investigators plan to use a multiplexed strategy to overcome tumor heterogeneity, which remains a challenge for drug development in this patient population, and antigen escape.

Ultimately, the experience of the initial three patients treated on BrainChild-01 suggests that repeated locoregional HER2-specific CAR T-cell dosing might be feasible and that correlative CSF markers might be valuable in assessing on-target CAR T-cell activity in the CNS, concluded Vitanza and coauthors.

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HER2-Specific CAR T Cells Induce Early Efficacy Without Dose-Limiting Toxicities in Pediatric CNS Tumors - OncLive

A mother’s love: Two years after devastating crash, Abby Roby has hope – London Free Press (Blogs)

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Wednesday marked the two-year anniversary of the day the lives of Abby Roby and her 19-year-old son Tristan Roby changed forever.

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But even on the anniversary of the date her son was seriously hurt in a hit-and-run crash, Abby doesnt dwell on the past. Instead, after months of up and downs and several stays in hospital, shes looking forward to what she hopes will be the next step in her sons recovery a stem cell treatment.

Tristan is starting to get back, so now its just a hope that he stays healthy and keeps going and that the stem cells kind of help push things along, she said.

Tristan, a Sir Wilfrid Laurier secondary school student, was injured on July 21, 2019, when he and a friend were riding their bikes on Exeter Road near Wonderland Road and he was struck by a vehicle.

Tristan, then 17, suffered serious brain damage as a result of the collision, which kept him on a respirator for 44 days and in hospital for more than three months. Other injuries included a compound fracture to his left leg, two bruised lungs, damage to his jaw. The damage kept him in a coma for weeks.

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The driver of the car that hit him stopped momentarily and then took off.A witness followed the vehicle and detained a fleeing passenger.

Police found the vehicle in a nearby parking lot, but the driver had fled. Six months later, London police charged Jesse Aron Bleck, then 26, with failing to stop at the scene of an accident causing bodily harm and two counts of driving while prohibited. Pretrial in the case is slated to begin early next year.

As with many of his treatments, the COVID-19 pandemic has delayed Tristan receiving the stem cell treatment, which would be administered in Michigan.

Besides his own condition Tristan was recently diagnosed with post-traumatic Parkinsons disease and spent several days in hospital both Abby and Tristan were waiting to get their two shots of a COVID-19 vaccine.

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Now, their hopes are set on the U.S. easing some of its restrictions to make the trip easier. American officials announced on Wednesday they are extending its land border restrictions until Aug. 21.

Im hoping that if everything works out, well get in there in August, Abby said.

Money for the treatment was raised earlier this year thanks to the support of Brian Vollmer, vocalist and founding member of the rock band Helix. He organized a telethon-type event, raising $17,000.

Though Tristan remains bedridden, he still shows signs of the outgoing young man he was before his injuries, Abby said.

I brought up his guitar the other day, and Im like, Oh, remember this guitar? and he was strumming it, she said.

The long hospital stays between December and March, they really, like, put him back in his recovery, but hes standing again and hes sitting and hes much more alert.

jjuha@postmedia.com

Twitter.com/JuhaatLFPress

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A mother's love: Two years after devastating crash, Abby Roby has hope - London Free Press (Blogs)

Roswell Park Team Shows Dendritic-Cell Vaccines Can Be Paired With Standard Therapy for Breast Cancer – Newswise

Newswise BUFFALO, N.Y. A research team led by Fumito Ito, MD, PhD, FACS, of Roswell Park Comprehensive Cancer Center reports new data on the promise of combining standard treatment for breast cancer with a particular form of cancer immmunotherapy dendritic-cell (DC) treatment vaccines. This study, published in the Journal for ImmunoTherapy of Cancer, is the first to demonstrate that in situ dendritic-cell vaccines can improve the effectiveness of radiation therapy for some aggressive and treatment-resistant forms of breast cancer.

Although immunotherapy with primary conventional dendritic cells is a promising approach, obtaining a sufficient number of circulating conventional dendritic cells has proved difficult, says Dr. Ito, who is Associate Professor of Surgical Oncology at Roswell Park. Use of induced pluripotent stem cells (iPSCs) has been proposed to overcome that limitation, but the feasibility of this approach had not previously been demonstrated.

The teams results show that intratumoral administration of iPSC-DCs significantly enhanced antitumor efficacy of local irradiation, which is commonly incorporated into treatment plans for patients with breast cancer.To better understand the potential of this approach, Dr. Ito and colleagues conducted laboratory studies to assess the antitumor efficacy of intratumoral injection of iPSC-DCs, or dendritic cells derived from iPSCs, and radiotherapy in models of triple-negative breast cancer that have shown resistance to anti-PD-L1 checkpoint inhibition immunotherapy.

The researchers demonstrate that radiation therapy increased the trafficking of intratumorally injected iPSC-DCs to the tumor-draining lymph nodes and augmented the activation of tumor-specific T cells. Their work shows that this multimodal intralesional therapy can control growth of distant tumors and render some breast cancers responsive to anti-PD-L1 therapy

While our work to develop this strategy is at an early stage and will need to be studied further, we show that these two approaches, radiotherapy and intratumoral iPSC-DC administration, can work synergistically to control not only local tumor growth but also distant tumors. And we saw evidence of systemic tumor-specific immunological memory, suggesting a potential for long-term tumor control, says Dr. Ito.

This study sheds light on the antitumor efficacy of in situ administration of iPSC-DCs when integrated with radiotherapy against poorly immunogenic tumors. These findings align with another study from Dr. Ito and his team, recently published in Nature Communications, that showed potent systemic antitumor immunity caused by combinational multimodal intralesional therapy.

Currently, efficacy of immunotherapy against breast cancer is limited, adds Dr. Ito. Our hope is to improve clinical outcomes for patients with advanced unresectable and metastatic breast cancer.

This work, In situ delivery of iPSC-derived dendritic cells with local radiotherapy generates systemic antitumor immunity and potentiates PD-L1 blockade in preclinical poorly immunogenic tumor models, was supported by several grants from the National Cancer Institute (project numbers P30CA016056, K08CA197966, and R50CA211108), as well as the Melanoma Research Alliance, Sarcoma Foundation of America and Uehara Memorial Foundation.

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For an online version of this release, please visit: https://www.roswellpark.org/newsroom/202107-roswell-park-team-shows-dendritic-cell-vaccines-can-be-paired-standard-therapy

Roswell Park Comprehensive Cancer Center is a community united by the drive to eliminate cancers grip on humanity by unlocking its secrets through personalized approaches and unleashing the healing power of hope. Founded by Dr. Roswell Park in 1898, it is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. Learn more at http://www.roswellpark.org, or contact us at 1-800-ROSWELL (1-800-767-9355) or [emailprotected].

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Roswell Park Team Shows Dendritic-Cell Vaccines Can Be Paired With Standard Therapy for Breast Cancer - Newswise

Introducing the 3D bioprinted neural tissues with the potential to ‘cure’ human paralysis – 3D Printing Industry

Researchers at the Chinese Academy of Sciences and University of Science and Technology of China have devised a novel bioprinting-based method of curing previously untreatable spinal cord injuries.

Using a custom bio-ink, the Chinese team have managed to 3D bioprint neural stem cell-loaded tissues capable of carrying instructions via impulses from the brain, much like those seen in living organisms. Once implanted into disabled rats, the scaffolds have shown the ability to restore movement in paralyzed limbs, and the scientists now believe their approach could find human applications in future.

There is no known effective cure for spinal cord injury, Zhijun Zhang, a nanobiomedical engineer at the Chinese Academy of Sciences told the Scientist. The 3D bioprinting strategy weve developed, may represent a general and versatile strategy for rapid and precise engineering of the central nervous system (CNS), and other neuronal tissues for regenerative medicine.

The SCI injury conundrum

A Spinal Cord Injury or SCI is a blanket term used to describe any damage caused to the bundle of cells and nerves that send signals to and from the brain along the human spinal cord. While the damage itself can be caused either by direct injury, or from bruising to the surrounding vertebrae, the result is often the same: a partial or complete loss of sensory and locomotor function below the affected area.

While theres no current known cure for SCI, a number of promising cell-based therapies are now being developed, with the regeneration of functional neurons seen as central to their future success. In effect, such approaches involve re-establishing links between neurons throughout the injured area in order to restore nerve functionality, but repairing damaged cells continues to be problematic.

Where neural stem cells have previously been implanted into SCI sites, theyve also shown poor viability and uncontrolled differentiation, leading to low therapeutic efficacy. More recent efforts have seen scientists bioprint cell-loaded scaffolds, capable of creating a suitable microenvironment in which neurons can flourish, yet this has raised further issues around printability and initiating cellular interaction.

To get around these problems, the Chinese researchers have now developed a novel bio-ink that gels together at body temperature to prevent neurons from differentiating into cells that dont produce electrical impulses, and can be 3D bioprinted into scaffolds that not only mimic the white matter appearance of the spine, but encourage cell-to-cell interactions.

A paralysis cure in-action

To begin with, Zhang and his team formulated their bio-ink from natural chitosan sugars, as well as a mixture of hyaluronic acids and matrigel, before combining them with rat neural stem cells. The scientists then used a BioScaffolder 3D bioprinter to deposit the resulting concoction into cell-laden scaffolds, which were later stored in culture plates for further testing.

Prior to their implantation, the teams different samples were incubated for three, five and seven days respectively, during which they proliferated and formed connections. Interestingly though, the researchers found that the higher the concentration of hyaluronic acid, the lower levels of interaction they observed, showing that their bio-ink can be tweaked to achieve desired tissue characteristics.

When injected into paraplegic lab rats, the scaffolds exhibited a cell viability of 95% while promoting neuron regeneration to the point that they enabled the rats to regain control over their hind legs. Over a 12-week observation period, the treated animals also showed a revived ability to move their hips, knees and ankles without support, and kick pressure sensors with markedly enhanced muscle strength.

As a result, the scientists have concluded that their approach offers a versatile and powerful platform for building precisely-controlled complex neural tissues with potential human applications, although they concede that more precise regulation of cell differentiation will be needed to achieve this, in addition to further testing on more clinically-relevant injury models.

Overall, this study clearly demonstrated for the first time the feasibility of the 3D bioprinted neural stem cell-laden scaffolds for SCI repair in-vivo, concluded the team in their paper, which, we expect, may move toward clinical applications in the neural tissue engineering, such as SCI and other regenerative medicine fields in the near future.

3D bioprinting in CNS treatments

Thanks to constant advances in flexible electronics and 3D bioprinting technologies, its now becoming increasingly possible to produce neural implants, with the potential to treat complex CNS injuries. Last year, a project started at TU Dresden led to the creation of 3D printed neural implants, capable of linking the human brain to computers as a means of treating neurological conditions such as paralysis.

In a similar study, engineering firm Renishaw has worked with pharmaceuticals expert Herantis Pharma to assess the performance of its 3D printed neuroinfuse drug delivery device. Designed to deliver intermittent infusions into the parenchyma, an organs functional tissue, the platform could be used as a future treatment for Parkinsons disease.

With regards to treating spinal injuries specifically, researchers at the University of California San Diego have also managed to repair spinal cord injuries in rats. By implanting 3D printed two-millimeter-wide grafts into test subjects, the team have been able to facilitate neural stem cell growth, restore nerve connections and ultimately help recover limb functionality in rodent test subjects.

The researchers findings are detailed in their paper titled 3D bioprinted neural tissue constructs for spinal cord injury repair. The study was co-authored by Xiaoyun Liu, Mingming Hao, Zhongjin Chen, Ting Zhang, Jie Huang, Jianwu Dai and Zhijun Zhang.

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Featured image shows the researchers 3D bioprinted scaffolds after 7 and 21 days culturing. Images via the Biomaterials journal.

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Introducing the 3D bioprinted neural tissues with the potential to 'cure' human paralysis - 3D Printing Industry