They’ve been likened to “giving patients a living drug” against cancer cells—genetically engineered T cells that selectively identify tumor cells and become super-activated upon binding to these cells. Known as chimeric antigen receptor (CAR) T-cell therapy, this form of immunotherapy has evolved into a mainstay to treat a variety of blood cancers, such as acute lymphoblastic leukemia, some types of large B-cell non-Hodgkin lymphoma, and most recently multiple myeloma.
Today, several hundred clinical trials involving CAR-T cells are ongoing throughout the world with six CAR T-cell therapies now approved by the FDA. While the use of CAR-T cells has been a notable accomplishment, concerns remain over its high cost, variable product quality, and the logistics of product manufacturing and delivery.
Some evidence suggests that about one-quarter of cancer patients slated to receive CAR-T therapy have a progression of their disease before they can be treated, with many waiting well over 3 weeks for delivery of a commercial CAR-T product. At the Sheba Medical Center in Israel, patients have access to in-house CAR T-cell therapy. This allows the T cells to remain better preserved and all the processing to be performed within 10 days.
Arnon Nagler, MD, MSc, is President of the Hemato-Oncology Center at Sheba Medical Center in Tel-Hashomer, Israel, as well as Professor of Medicine at the Tel Aviv University. He has worked in the field of bone marrow transplantation for hematological malignancies for the last quarter century and is a leading spokesperson for the development of in-house CAR T-cell therapy.
Oncology Times: What drove you and others at Sheba Medical Center to set up your own in-house center to produce CAR-engineered T cells instead of relying on commercial products? How long did this process take?
Nagler: “The main motivations for us instituting point-of-care production of CAR-T cells at Sheba were to increase affordability and accessibility, the latter of which is becoming increasingly challenging due to the high demand for commercial CAR products. Point-of-care in-house production of CAR-T cells can help overcome these two main obstacles.
“CAR T-cell therapy has seen unprecedented efficacy in patients with very advanced hematological malignancies that have already exhausted every other possible available therapy, providing hope for the first time to these patients. In-house manufacturing of CAR T-cell products has a similar success rate to pharma-produced commercial CAR, with almost no manufacturing failures. Managing the entire process on-site, allows for a substantially shorter vein-to-vein time (time from leukapheresis until CAR administration), reducing the process to about 10 days, which spares the patient the necessity of bridging therapy, correlating with improved outcomes.
“Of course, in-house production of CAR-T cells is increasing the accessibility and drastically reducing the cost for patients. Additionally, in-house CAR T-cell therapy enables attending clinicians to address urgent clinical demands or acute changes in patients’ clinical status. Lastly, point-of-care CAR-T cells eliminate the need for cryopreservation of the CAR T-cell products, preserving cell quality and potency of the treatment.”
Oncology Times: Have you been surprised by patient outcome statistics (ie, OS/PFS) for those having access to in-house CAR T-cell therapy at Sheba versus commercial centers?
Nagler: “Not at all. Before launching the in-house CAR T-cell program, we spent 9 months working on a regulatory package and performed dry and wet experiments in the lab with cell lines, and subsequently with primary samples from consenting patients. Our results did not differ from the currently approved commercial CAR-T products. The Minister of Health checked every possible angle of the point-of-care CAR T-cell program before approving it, so we expected the outcomes of Sheba’s in-house CAR-T cells not to differ from those of commercial CARs.”
Oncology Times: Cytokine release syndrome and neurological toxicities are a concern with commercial CAR T-cell products. How is Sheba addressing this concern?
Nagler: “Sheba’s in-house CAR-T program, as all other CARs programs, operates in accordance with the international and European recommendations established by key experts in the field, which experts from our department were part of (Ann Oncol 2022; doi: 10.1016/j.annonc.2021.12.003; Haematologica 2020; doi: 10.3324/haematol.2019.229781; Biol Blood Marrow Transplant 2019; doi: 10.1016/j.bbmt.2019.08.015; Biol Blood Marrow Transplant 2019; doi: 10.1016/j.bbmt.2018.12.068).
“In case of an adverse event, we have prepared and educated the team of physicians, nurses, and attending and on-call doctors about these concerns. We also have had meetings with the relevant physicians from the hospital’s intensive care, neurology, and radiology units, as well as our clinical pharmacists, lab clinicians, and others. Sheba has stocked the necessary materials and pharmacologic compound tocilizumab in designated places in the department and the necessary staff, including night shift nurses and on-call doctors, are well prepared should they need to be administered.
Oncology Times: Last year, you reported some encouraging but early results for the treatment of Richter’s transformation. Can you provide an update on this work?
Nagler: “Yes, of course. Richter is a devastating disease with very poor prognosis and outcomes and very limited therapeutic options. In our American Society of Hematology (ASH) frontal presentation, we reported nine patients with Richter transformation that we treated with in-house point-of-care CAR-T cells. Six of nine achieved remission and, in some of them, the CAR therapy was followed by allogeneic transplantation.
“Since then, we have treated an additional two patients. Out of the initial six responding patients, three relapsed and two of them received additional therapies. Some new data are emerging combining ibrutinib, a Bruton’s tyrosine kinase, with CAR T-cell therapy that may improve results.”
Oncology Times: What lessons can others learn from your experience as they seek to set up their own in-house CAR-T center?
Nagler: “Establishing point-of-care CAR T-cell programs is doable and achievable. In-house manufacturing of the CAR-T cell creates almost no production failures and is a substantially shorter process. It is manageable and safe with comparable efficacy and therapeutic yield and [has a] similar success rate to the pharma-based commercial CARs.”
Oncology Times: Can you briefly update advances to use CAR T-cell therapy for solid tumors?
Nagler: “As opposed to hematologic malignancies like acute lymphocytic leukemia, malignant lymphoma, and multiple myeloma—in which CAR T-cell therapy revolutionized the field with unprecedented results—the field is only in its infancy with solid tumors and the challenges are enormous. These include the absence of antigen-like CD19 that detects lymphatic malignancies with high efficacy and very low off-target effects. Additionally, in contrast to liquid tumors, it is much more challenging for the CAR-T cells to penetrate solid tumors. But the field is progressing and there are already ongoing clinical studies of using CAR T-cell therapy for glioblastomas, pancreatic tumors, colorectal cancers, and others.”
Oncology Times: Are there any innovations underway at Sheba to improve your in-house capabilities in CAR T-cell therapy for patient care?
Nagler: “We opened a new CAR T-cell program for multiple myeloma with point-of-care anti-B-cell maturation antigen (BCMA) CAR-T cells, and we’ve already treated 40 patients from Israel and abroad with good results. We have a program with CD19 CAR-T cells for relapsed refractory acute myeloid leukemia (AML) with t (8;21) (q22; q22.1). We treated six patients in this clinical trial and four out of six went into complete remission. We additionally have just submitted an abstract reporting this innovative first-in-human therapy to the next European Hematology Association meeting, which will take place in June 2023 in Frankfurt, Germany.
“We also tried to develop strategies for patients who do not respond to or relapse post CAR-T cell therapy and just published two papers on the subject in the last few months (Leukemia 2023; doi: 10.1038/s41375-022-01739-2; Transplant Cell Ther 2023; doi: 10.1016/j.jtct.2022.10.026). We are also trying with our MSKCC colleagues to develop a way to predict response to CAR T-cell therapy in lymphoma ahead of time, which was presented at the 2022 American Society of Hematology Annual Meeting.”
Published April 20, 2023 Oncology Times