Recent Advances in CAR-T Therapy

Abstract

Chimeric antigen receptor T cell therapy is used to treat hematological malignancies which are refractory to standard therapy. It is a form of immunotherapy in which a patient’s T cells are programmed to act against tumor cells. We discuss the process of manufacturing CAR-T cells, the common side effects of therapy, and the recent emerging risk of T-cell malignancies after treatment.

Editorial

Chimeric antigen receptor T cell (CAR-T) therapy is a form of immunotherapy that has enabled patients with previously incurable hematological cancers to go into remission. Currently marketed CAR-T therapies include Yescarta, Tecartus, Kymriah, Breyanzi, Carvykti, and Abecma. Indications are acute lymphoblastic leukemia, large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and multiple myeloma.^1-3 CAR-T therapy is indicated for relapsed or refractory non-Hodgkin lymphoma after at least 2 lines of therapy, which may include chemotherapy or stem cell transplant (SCT). CAR-T therapy was first approved for commercial use in 2022 after which it has become an established treatment modality in patients with refractory cancer. With its now widespread use, different side effects are emerging. Recently the U.S Food and Drug Administration issued a warning regarding the risk of T-cell malignancies after therapy, a topic discussed below.

CAR-T cells are genetically modified T cells that are programmed to have synthetic receptors to which specific tumor antigens can bind based on the biomarkers, CD19 and BCMA. The CAR-T cells then act as active drugs to mount a reaction to kill the tumor cells.^1,4 The process starts by leukapheresis of the patient’s mononuclear cells from the peripheral blood. These cells are then sent to a facility where they are activated and the target gene is transduced into them using a lentiviral or retroviral vector. These cells are replicated to achieve the target dose for treatment and sent back to the hospital where the infusion is to take place. ⁵ Before infusion, lymphodepletion chemotherapy with agents such as cyclophosphamide and fludarabine is done to reduce the patient’s immune cells and make space for the CAR-T cells. This increases the expansion, persistence, and efficacy of CAR-T cells. Side effects of lymphodepletion include pancytopenia, immunosuppression leading to various infections, and individual toxicities of the agents used. Infusion is through central venous access and most commonly occurs in the hospital due to the intense monitoring needed for side effects.

The most common side effects of CAR-T therapy are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is due to the release of cytokines on activation of CAR-T cells. It can cause fever, hypotension, hypoxia, and severe organ dysfunction. ⁶ C reactive protein, ferritin, D dimer, fibrinogen, and triglycerides are obtained to monitor CRS. It is graded from 1 to 4, depending on the degree of hypoxia and hypotension, the need for supplemental oxygen or vasopressors, and fever. Mild CRS (grades 1 and 2) is managed through intravenous fluids, antipyretics, and antihistamines. Severe CRS (grades 3, 4 and some cases of 2) is treated with interleukin 6 antagonists like tocilizumab and corticosteroids. CAR-T-related encephalopathy can present with confusion, agitation, tremors, seizures, and obtundation. It is assessed through the CARTOX-10 scale. The mechanism may be due to increased permeability of the blood-brain barrier (BBB) which causes cytokines and CAR-T cells to enter the nervous system. ⁷ Management includes corticosteroids, anti-seizure medications, and supportive care. Interleukin 6 antagonists are not useful for ICANS as they do not permeate the BBB. ⁸ Both CRS and ICANS can be life-threatening and may need to be managed in the intensive care unit.

Recently the FDA stated that CAR-T therapy may increase the risk of T cell lymphomas.^1,3 Patients who undergo CAR-T therapy already have an increased risk of secondary cancer due to their primary cancer and past treatment with radiation, chemotherapy agents, or SCT. The risk factors that predispose them to their primary cancer may also make them susceptible to acquiring a secondary malignancy. However, the T cells found in the lymphomas were genetically similar to the CAR-T cells, making them the source of the lymphoma. It is believed that the risk is due to the use of viral vectors in the process of manufacturing the therapy, which may activate oncogenes and disrupt tumor suppressor genes. ³ The risk of secondary malignancies was already included in the CAR-T labels but FDA now mandates boxed warnings regarding CAR-positive T-cell malignancies. It is advised to closely monitor patients after therapy and report any side effects to the FDA.

CAR-T therapy is evolving, and multiple clinical studies are being done. Ongoing clinical trials are investigating the efficacy of CAR-T therapy in malignancies like breast, pancreatic, and lung. ⁹ CAR-T therapy for solid tumors is challenging due to tumor heterogeneity, difficult tumor infiltration, and lack of a single tumor antigen that can be targeted. Various tumor cell targets are being investigated so that different types of tumors can be targeted with CAR-T therapy. Bi-specific CAR T-cells are being engineered which can express 2 different CARs, enabling them to target 2 different tumor-associated antigens simultaneously. This can also help with tumor antigen escape which is a mechanism of CAR-T resistance where there is a loss of the targeted antigen from tumor cells causing resistance to therapy. To reduce toxicity, trials are underway which show that administration of prophylactic corticosteroids may prevent or delay CRS, without affecting the efficacy of treatment. Side effects of CAR-T therapy need to be closely monitored. With the number of people who have gone into remission with CAR-T therapy and current ongoing clinical trials, the future of CAR-T therapy looks promising.