CAR-T Cells: The Next Era in Immuno-Oncology

An update on immunotherapies and the potential impact of chimeric antigen receptor (CAR)-T cells on oncology care.
Published Online: February 14, 2017
Bruce A. Feinberg, DO; Jennifer Fillman, MBA; Justin Simoncini, MBA, MPH; and Chadi Nabhan, MD, MBA, FACP
FOR THE THIRD CONSECUTIVE YEAR, the editors of Evidence-Based Oncology (EBO)™ are dedicating the February issue to immuno-oncology (I-O), and Cardinal Health has been a part of the conversation in each of the 3 issues. We marvel at the fact that it is a mere 5 years since the FDA approval of the first I-O of the modern era, the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor ipilumumab1; 2 years since the approval of the first 2 programmed death-1 (PD-1) inhibitors (nivolumab and pembrolizumab)2,3; and just months since the approval of the first programmed death-ligand 1 (PD-L1) antagonist (atezolizumab).4 In such a relatively short time, these I-O therapies have:
• Garnered FDA approvals in 6 tumor types
• Received indications for adjuvant, first-line metastatic, and salvage disease
• Been combined for dual I-O therapy
• And, are likely to receive 5 additional tumor type approvals in the proceeding 12 to 18 months.

Key opinion leaders and subject matter experts openly conjecture the end of the chemotherapy era while the silence around precision medicine is deafening. More than half of all actively accruing cancer therapeutic trials involve I-O across 52 different malignancies as single agents, dual I-O regimens, and I-O in combination with chemotherapy and targeted therapy.

Our 2016 EBO™ article concluded with the statement: “Stakeholder adoption of I-O is no longer a question of ‘IF’ but a question of ‘WHEN.‘ Who will be treated, with ‘what’ types of cancer, in ‘which’ stage and for ‘how’ long remain unanswered questions.”5 A year later, many of these questions are already being answered as new ones emerge, as I-O is poised to become the backbone of modern cancer treatment. Chief among these questions is ‘What lies beyond CTLA-4, PD-1, and PD-L1 in the future of I-O therapeutics?’ Most I-O treatments do not directly attack the tumor, rather, they mobilize the immune system to recognize and destroy the tumor. This can be achieved using various approaches, including antibodies, peptides, proteins, small molecules, adjuvants, cytokines, oncolytic viruses, bispecific molecules, and cellular therapies.

We believe the next I-O frontier to move from the bench to the bedside is cellular therapy in the form of chimeric antigen receptor (CAR)-T cells. In the first published trial from the University of Pennsylvania (U-Penn), 27 of 30 (90%) relapsed and refractory (R/R) patients with acute lymphoblastic leukemia (ALL) experienced complete remission 1 month after CAR-T infusion—22 (73%) of them had no evidence of minimal residual disease (MRD).6 Rapid, complete, and durable responses in highly refractory patients make CAR T a potential game-changer for cancer therapy, but the issues impacting stakeholder adoption for ex-vivo activated cellular I-O are significantly more complex than anything we’ve seen before.7

History and Development of CAR-T Technology

First and foremost in the discussion is recognizing that CAR T does not represent a drug, but, rather, a complex therapeutic process. Whereas most of the previously commercialized I-O interventions—from interferons to interleukins to checkpoint inhibitors—are essentially drug therapies, CAR T is operationally more similar to hematopoietic stem cell transplantation (HSCT). In fact, the concept of CAR T has its origin in the allogeneic bone marrow transplantation (BMT) of ALL. More than a quarter century ago, observations of durable remissions in patients with ALL, post BMT, who suffered graft versus host disease (GVHD) led to the understanding that donor or grafted T-cell recognition of malignant host lymphoblasts could impart long-term disease control (graft versus leukemia effect).8 The hypothesis generated was: if autologous T cells could be conditioned/manipulated to recognize malignant cells, then tumor control could be achieved without the negative consequences of GVHD.

When mild, GVHD is a complex chronic disease in which the grafted immune system is at war with the host organs; however, GVHD is life-threatening when severe. It would be critical to solve the problem of GVHD should any immune cellular therapy be successful. One method developed to create tumor recognition without the complications of GVHD involved reprogramming autologous T cells to identify and eliminate malignant cells through tumor-specific antigen recognition. The reprogramming required harvesting T cells from the patient via apheresis, transporting the cells to a wet lab where they could be chemically modified, and then altering the cells by linking the extracellular antigen recognition domain from a monoclonal antibody fragment to the T cell’s intracellular signaling domains.9 This newly modified autologous T-cell antigen receptor complex would then be a fusion, or chimera, of 2 proteins, or CAR. While still in the lab, the newly created CAR-T cells could then be incubated, or more technically, activated, to expand their number. Once adequately expanded, the CAR-T cells could be re-infused into the patient, but only after the patient is primed with chemotherapy to deplete their own circulating lymphocytes, which might dilute the CAR-T cells’ effectiveness. T cells engineered to express such CARs engage an antigen on a tumor cell through the extracellular antibody domain, thereby activating the T cells in a major histocompatibility complex–independent manner.8 Stated less scientifically, CAR-T cells can stimulate potent cytotoxic immune responses without the negative consequences of GVHD.



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