Stem Cell Clinic

Off-the-Shelf NK Immunotherapy Is Safe and Promising in B-Cell NHL With Chemotherapy and Transplant – Targeted Oncology

Early antitumor activity was seen with cord bloodderived natural killer (NK) immunotherapy in combination with high-dose chemotherapy and autologous stem cell transplant (ASCT) in patients with B-cell non-Hodgkin lymphoma (NHL), according to early results from a phase 2 trial (NCT03019640) presented in a poster during the 2021 Transplant & Cellular Therapy Meetings.

The investigators evaluated the potential of the novel cellular cord bloodderived NK immunotherapy in patients with B-cell NHL who are undergoing high-dose chemotherapy and ASCT. They chose CB units for NK cell expansion on artificial antigen presenting cells and without human leukocyte antigens (HLA) matching to provide increased expansion and make the treatment off-the-shelf capable.

The study enrolled patients who were aged 15 to 70 with B-cell NHL, excluding primary central nervous system lymphoma, who were candidates for high-dose chemotherapy and ASCT. Patients were required to have adequate end-organ function, an ECOG performance status of 0 or 1, and prior apheresis of 2 x 106 CD34+ cells/Kg in order to be eligible.

Those with prior whole brain irradiation, active hepatitis B, evidence of cirrhosis or high-grade liver fibrosis, active infection, HIV infection, or received radiation therapy within the past month were excluded from joining the trial.

Patients were given intravenous (IV) carmustine over 2 hours 12 days prior to transplant, IV etoposide twice daily over 3 hours and IV cytarabine twice daily over 1 hour for days 11 to 8 prior to transplant, IV melphalan over 30 minutes 7 days prior to transplant, oral lenalidomide (Revlimid) once daily for days 7 through 2 prior to transplant. Additionally, patients who are CD20-positive received IV rituximab (Rituxan) over 3 hours for days 13 through 7 prior to transplant.

Then patients received cord bloodderived expanded allogeneic NK cells intravenously over 1 hour on day 5 prior to ASCT. Five days following ASCT, patients started received daily subcutaneous filgrastim.

The primary end point was 30-day treatment-related mortality (TRM) and secondary end points were relapse-free survival (RFS), overall survival, and NK cell persistence.

Study authors, led by Yago L. Nieto, MD, PhD, in the Department of Stem Cell Transplantation, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center in Houston, provided an update on data for 20 of the enrolled patients in the study. Patients were enrolled between December 2017 and July 2020. One patient experienced rapid tumor progression during culture of NK cells and thus was not treated in the study.

The median age of the 19 treated patients was 60 years (range, 33-70) with the majority (73.7%) being male and having diffuse large B-cell lymphoma (DLBCL; 84.2%); the 3 remaining patients had mantle cell lymphoma (n = 2) or follicular lymphoma (n = 1). More than two-thirds (68.4%) of patients had relapsed disease whereas the 2 patients with MCL were being treated in the frontline setting and 4 patients had primary refractory disease. The median number of prior lines of therapy was 2 (range, 1-4).

Response assessed through PET at ASCT was a complete response for 78.9%, partial response for 15.8%, and progressive disease for 5.3%. Nine patients had 1/6 HLA match of cord blood at DR, 6 had 1/6 match at B, 3 had 1/6 match at A, and 1 had 2/6 match at B and DR.

Cord bloodderived NK cells were expanded a median of 1552-fold (range, 317-4767) with the infused NK product comprising a CD3-CD16+CD56+ phenotype for a median of 98.9% (range, 97.6%-99.5%) of the cells. The cord bloodderived NK cells had a median viability of 96.5% (range, 92%-98%). In the peripheral blood, NK cells were detectable for a mean of 2 weeks (range, 2-3).

For weeks 1 through 3, the cord bloodderived NK cells showed a higher percentage of NKG2D and NKp30 activation receptors than the patients own NK cells; the study authors noted that this indicated an effector phenotype. Additionally, NK persistence was found not to be impacted by the degree of HLA mismatch.

At a median follow-up of 18 months (range, 4-340), the RFS rate was 68% and the OS rate was 84%. Eleven of the 16 patients (68.8%) with DLBCL are still in remission.

The study authors concluded that expanded and highly purified cord bloodderived NK immunotherapy was safe and promising in combination with high-dose chemotherapy and ASCT in patients with B-cell NHL.

Reference:

Nato Y, Kaur I, Hosing C, et al. Immunotherapy with ex vivo-expanded cord blood (CB)-derived nk cells combined with high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) for B-cell non-hodgkins lymphoma (NHL). Presented at: 2021 Transplant & Cellular Therapy Meetings; February 8-12, 2021; Virtual. LBA15.

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Off-the-Shelf NK Immunotherapy Is Safe and Promising in B-Cell NHL With Chemotherapy and Transplant - Targeted Oncology

Braunschweig Makes the Case for Earlier Use of CAR T-Cell Therapy in DLBCL – OncLive

CAR T-cell therapy has shown robust responses and curative potential in patients with diffuse large B-cell lymphoma (DLBCL), regardless of cytogenetics or age, said Ira Braunschweig, MD, who added that the early use of tocilizumab (Actemra) and steroids has made it all the more likely that the modality could be moved to the up-front setting.

Its important to distinguish [between] the options a patient with aggressive lymphoma has, [particularly when it comes to] distinguishing between options that could help them versus options that can cure them, and CAR T-cell therapy stands alone as an option that could cure patients, said Braunschweig.

In an interview withOncLiveduring the 2020 Institutional Perspectives in Cancer webinar onhematologic malignancies, Braunschweig, director of the Stem Cell Transplant Program, clinical program director of Hematologic Malignancies at Montefiore Medical Center, and associate professor in the Department of Medicine (Oncology) at Albert Einstein College of Medicine, discussed the utility of CAR T-cell therapy in lymphoma and the rationale behind moving the modality to the up-front setting.

Braunschweig Its difficult to say, as far as efficacy, which [product] is better than the other because theyve never been compared head-to-head and probably never will be. It does seem that tisagenlecleucel [can be given as an] outpatient [therapy], which is nice.

Based on the data we have so far, we know that [these patients] respond very favorably [compared] with other subgroups. A [patient with] double hit or triple[-hit lymphoma] is not someone who will not respond [to the therapy], which is extremely encouraging.

We learned that axi-cel is as good as advertised, and [comparable with] what we saw on the clinical trial. Patients do not have to be in perfect condition to be able to tolerate and benefit from [the product], which is extremely importantnot every one of our patients is a marathon runner.

There was no difference between the older and younger populations [in terms of] response, which is also very encouraging, because we treat a lot of older patients. [Knowing] that [the product] is effective in that group [of patients] as well is great.

[CAR T-cell therapy is a fantastic option for] a [patient with] primary refractory or multiply relapsed [disease] or [a patient with] relapsed [disease] posttransplant. For a certain number of patients, [CAR T-cell therapy] will likely be a curative therapy. [CAR T-cell therapy] has been truly a game changer for these patients.

For a chemotherapy-sensitive patient, autologous transplant is still the standard of care, largely, in part because we have decades of experience with those patients. When we get to a primary refractory patient, it would seem that CAR T-cell therapy is the clear choice. Only a few years ago, we used to offer a [patient with] relapsed [disease] post-autologous transplant an allogeneic transplant, and there are data that that treatment could be curative for such a patient.

However, we have to recognize that there is a lot of graft-versus-host-disease and ongoing health issues [that accompany] allogeneic transplant. With CAR T-cell therapy, if [patients] get through the first couple of weeks of toxicities, theres a lot less of a concern about their long-term health. In fact, with CAR T-cell therapies, data are coming out that we can treat these toxicities effectively without worrying about abrogating the antitumor response, which makes it even more attractive.

There are data that early tocilizumab can, at the first fevers, abrogate the CRS toxicity without abrogating the antitumor effect. Even [early use of] steroids, which are lymphocyte killers, is supported by data for neurotoxicity and does not seem to abrogate the antitumor response. If we could [treat patients even] earlier [with these interventions] and not have them become confused, or [enter a certain coma level], that could be even better.

Once we know that its extremely effective for [patients with] relapsed/refractory [disease], and we know that its effective for [patients with] high-risk genetic genetics, perhaps we could offer those patients up-front CAR T-cell therapy after some cytoreduction with chemotherapy as a consolidation approach.

If we know a patient has a high risk of relapse, it makes perfect sense to offer [CAR T-cell therapy] to them up front. Its an effective therapy for those patients. If we know that theyre ultimately going to fail [treatment], then why wouldnt we [offer it to them up front? For those patients that could be cured with R-CHOP, R-CHOP is still probably the way to go. [Well have to] figure out whos not going to do well with R-CHOP [and may be a candidate for CAR T-cell therapy up front].

[Theres research evaluating] dual targets. Can we combine novel agents with CAR T-cell therapy to increase its effectiveness? Maybe well offer more than one infusion of CAR T-cell therapy. If so, there might be a tandem CAR T-cell therapy one day. Those things are being looked at.

The most important point is that a [patient with] multiply relapsed [or] even refractory lymphoma [should be considered for CAR T-cell therapy] as a curative option for treatment.

We have a robust CAR T-cell therapy unit. Weve treated the first [patient] in the nation with the FDA-approved [brexucabtagene autoleucel (Tecartus)] for mantle cell lymphoma with excellent results, and we have ongoing trials with CAR T-cell therapy in multiple myeloma as well.

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Braunschweig Makes the Case for Earlier Use of CAR T-Cell Therapy in DLBCL - OncLive

Creative Medical Technology Holdings Files Patent on Prevention of Organ Transplant Rejection using ImmCelz – PRNewswire

PHOENIX, Feb. 16, 2021 /PRNewswire/ --(OTC CELZ) Creative Medical Technology Holdings, Inc. announced today filing of a patent application covering the use of ImmCelz regenerative cell therapy for preventing rejection of transplanted organs. ImmCelz is a cellular therapy that prevents pathological immunity and inflammation while at the same time inducing regeneration of damaged tissue. Mechanistically ImmCelz has been shown to function through stimulation of T regulatory cells1 and producing the regenerative protein Hepatocyte Growth Factor (HGF)2. The patent demonstrates that ImmCelz may have the potential to inhibit chronic graft rejection, which is the major cause of organ loss.

"The concept of immunological tolerance has been around for more than a Century since the days of Peter Medawar," said Dr. Amit Patel, Board Member of the Company and co-inventor of the patent. "Unfortunately, transplant recipients, which include some of my patients, need to take global immune suppressive medication to reduce immune-mediated rejection of the organ. These medications, despite having made organ transplantation a reality, have potential side effects including various infections due to suppression of immunity. ImmCelz is being developed to induce immunological tolerance, which if achieved would allow for organ transplantation without need for continuous immune suppression."

Sales of immune suppressants, which are used after transplants to prevent patients from rejecting their organs exceeded 4 billion dollars in 20183.

"To date the Company has reported therapeutic activity of ImmCelz in models of rheumatoid arthritis4, stroke5, type 1 diabetes6, kidney failure7 and liver failure8," said Timothy Warbington, President and CEO of the Company. "Demonstration of enhancing graft survival in organ transplantation allows for a whole new area of medical progress. Our scientists suggest the superior efficacy of ImmCelz for organ transplantation is that the cellular therapy suppresses rejection, while at the same time regenerates the organ after transplantation. It is known that the process of transplantation causes harm to the organ."

"It is our goal to continue to broaden our intellectual property portfolio by patenting technologies that our scientific team determines to be worthwhile and in the area of our core concentration," Mr. Warbington said further.

About Creative Medical Technology Holdings Creative Medical Technology Holdings, Inc. is a commercial stage biotechnology company specializing in regenerative medicine/stem cell technology in the fields of immunotherapy, urology, neurology and orthopedics and is listed on the OTC under the ticker symbol CELZ. For further information about the company, please visit http://www.creativemedicaltechnology.com.

Forward Looking Statements OTC Markets has not reviewed and does not accept responsibility for the adequacy or accuracy of this release. This news release may contain forward-looking statements including but not limited to comments regarding the timing and content of upcoming clinical trials and laboratory results, marketing efforts, funding, etc. Forward-looking statements address future events and conditions and, therefore, involve inherent risks and uncertainties. Actual results may differ materially from those currently anticipated in such statements. See the periodic and other reports filed by Creative Medical Technology Holdings, Inc. with the Securities and Exchange Commission and available on the Commission's website at http://www.sec.gov.

Creativemedicaltechnology.com http://www.StemSpine.com http://www.Caverstem.com http://www.Femcelz.com http://www.ImmCelz.com http://www.OvaStem.com

1Creative Medical Technology Holdings Identifies Mechanism of Action of ImmCelz Stroke Regenerative Activity (prnewswire.com) 2Creative Medical Technology Holdings Identifies and Files Patent on Novel Mechanism of ImmCelz Therapeutic Activity (prnewswire.com) 3Organ Transplant Immunosuppressant Drugs Market Size Report, 2026 (grandviewresearch.com) 4Creative Medical Technology Holdings Reports Positive Preclinical Data on ImmCelz Immunotherapy Product in Rheumatoid Arthritis Model | BioSpace 5Creative Medical Technology Holdings Identifies Mechanism of Action of ImmCelz Stroke Regenerative Activity (prnewswire.com) 6Creative Medical Technology Holdings Announces Positive Data and Patent Filing Using ImmCelz to Treat Type 1 Diabetes (prnewswire.com) 7Creative Medical Technology Holdings Files Patent based on Positive Data on Renal Failure using ImmCelz Regenerative Immunotherapy (prnewswire.com) 8Creative Medical Technology Holdings Announces Reversion of Liver Failure Using ImmCelz Personalized Cellular Immunotherapy in Preclinical Model | Nasdaq

SOURCE Creative Medical Technology Holdings, Inc.

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Creative Medical Technology Holdings Files Patent on Prevention of Organ Transplant Rejection using ImmCelz - PRNewswire