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Autologous CAR T therapy created a breakthrough treating blood cancers, but inherent limitations make it less accessible to those where the wait for cell manufacturing makes advanced patients more vulnerable.

Allogeneic CAR T cell therapy, an investigational therapy, may have the potential to revolutionize the field of cell therapy. Here, Dr. Shaji Kumar, professor of medicine at the Mayo Clinic and Dr. Rafael G. Amado, EVP of Research and Development, Chief Medical Officer at Allogene Therapeutics, discuss the potential of allogeneic CAR T therapy in multiple myeloma.

Dr. Shaji Kumar, professor of medicine at the Mayo Clinic

What are the current unmet needs in multiple myeloma?

Dr. Shaji Kumar: While there have been significant improvements in survival for multiple myeloma patients, three major stumbling blocks remain. First is the lack of any cure despite recent advances. Many patients continue to be on therapy until disease progression, which has a cumulative impact on both toxicities and cost of care. The second is patients with high-risk disease who do not appear to benefit with current therapies. The third is the treatment of relapsed/refractory (R/R) disease especially with hard-to-treat manifestations such as plasma cell leukemia and extramedullary disease.

Why is the time right for allogeneic cell therapy to be a new frontier in cancer treatment?

Dr. Rafael Amado: Evolving CAR T therapy requires overcoming a number of limitations inherent to manufacturing a patient’s own immune cells for treatment: long wait times, product heterogeneity, high cost individual manufacturing runs, limited ability to genetically engineer cells, and patients without a sufficient number of healthy cells to make an effective graft. Allogeneic T cells derived from healthy donors can be engineered with the goal to optimize antitumor effect, decrease exhaustion and be available off-the-shelf. This is particularly important in blood cancers where some patients may have rapidly progressing disease and cannot wait long enough to receive autologous therapy. In the last five years, rapid innovation in enhanced cell engineering technologies make investigating ways to overcome these limitations possible with allogeneic cell therapy, by allowing genetic editing beyond viral gene transfer. These edits can also incorporate genetic elements that may enhance the antitumor potency of these therapies.

What challenges are unique in treating multiple myeloma? What role can allogeneic CAR T therapy play?

Dr. Kumar: Current immunotherapy platforms, including autologous CAR T, provide proof of principle for the efficacy of immunotherapies in eradicating significant proportions of tumor burden. One of the challenges with current autologous CAR T approaches has been the time required to manufacture T cells during which the patient’s disease often requires control. This is particularly a problem in the late stage setting where the myeloma has become unresponsive to current therapies. Given rapidly progressing disease at this stage, many patients are unable to wait for any considerable amount of time for an effective therapy to be employed. In this setting, allogeneic CAR T therapy could clearly play an important role.

How do you think about innovation in allogeneic cell therapy, particularly in multiple myeloma?

Dr. Amado: Innovation requires applying insights from across our programs, such as cell manufacturing and dose, lymphodepletion, donor cell properties, genetic edits to improve activity and decrease exhaustion, redosing and consolidated dosing as we evaluate ways to optimize therapy. This is reflected in Allogene’s three-pronged strategy targeting B cell maturation antigen (BCMA). The first is ALLO-715, our investigational AlloCAR T therapy being studied for the treatment of R/R multiple myeloma in the UNIVERSAL Phase 1 trial. Initial data from this trial will be presented at this year’s American Society of Hematology Annual Meeting.

Our second centers on ALLO-715 in combination with an investigational gamma secretase inhibitor (GSI) to prevent the cleavage and shedding of BCMA from the surface of myeloma cells. In other studies, GSI has been shown to increase the malignant cell surface density of BCMA and reduce levels of circulating BCMA, thereby enhancing the activity of BCMA-targeted therapies. This is the type of innovation that may be needed to optimize the effect of anti-BCMA cell therapy to expand treatment options that further unlock the potential of cell therapy for these patients.

The third focuses on our investigational TurboCAR technology, which may have the potential to expand AlloCAR T cell viability while reducing cell dose requirements and overcoming exhaustion. The technology avoids the use of soluble products that could add to the toxicity of cell therapy. This technology may also open the door for AlloCAR T therapies in harder to treat hematologic malignancies and solid tumors. We are excited by what this technology may mean for next-generation AlloCAR T therapy in multiple myeloma and plan to initiate a clinical trial of ALLO-605, our first TurboCAR candidate, in this disease.

What should be the focus of research in CAR T therapy in multiple myeloma?

Dr. Kumar: The focus for future research should be improving the efficacy of CAR Ts for patients by targeting multiple antigens and developing CAR Ts that can provide a sustained immune response. Research should also focus on how to reduce the toxicity of the CAR T platform by optimizing lymphodepletion therapy and easing management of the inevitable immune-related toxicities.

What are the next steps in advancing allogeneic cell therapy?

Dr. Amado: Optimizing the potential benefits of allogeneic cell therapy means thinking beyond the confines of autologous therapy studies driven by inherent limitations in cell supply. Allogeneic cells can be engineered for off-the-shelf use to investigate special properties such as rendering specificity for multiple malignant cell antigens, decreasing rejection, changing cell properties to increase potency, and avoiding immunosuppressive elements of the tumor microenvironment. For instance, we are exploring how best to utilize ALLO-647, our investigational anti-CD52 lymphodepleting agent, with our AlloCAR T cells, which may potentially reduce rejection. There a myriad of molecular strategies that can be engineered and tested using modern gene editing approaches.

While significant work is ahead, I believe AlloCAR T therapy provides an incredible opportunity to explore powerful ways to provide cell therapy and potentially ameliorate toxicity to pave the way for outpatient treatment.

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