CAR-T Cell Therapies for Hematological Malignancies
Carlos Ramos, MD, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA
Authored by Paolo Strati, MD, MD Anderson Cancer Center, Houston, Texas, USA
Chimeric antigen receptor (CAR) T cells are a form of adoptive therapy employing autologous T cells engineered with an artificial receptor, able to recognize tumoral epitopes through an HLA-independent mechanism. Given the low activity observed with first generation CAR-T cells in B-acute lymphoblastic leukemia (B-ALL) and B-cell lymphoma, a co-stimulatory domain (CD28 or 4-1BB) was added to second generation CARs, significantly increasing their persistence in vivo and, as a consequence, improving their clinical efficacy. Early experience with second generation CAR-T cells also established the need for conditioning with both cyclophosphamide and fludarabine to decrease rejection and improve efficacy.
Three second generation CAR-T cell products, targeting CD19, have been tested in multicenter industry-sponsored clinical trials and two of them, axicabtagene ciloleucel or axi-cel (marketed as Yescarta) and tisagenlecleucel (marketed as Kymriah) have been FDA approved in 2017 and 2018, respectively. The activity observed with these agents in heavily pre-treated B-ALL and B-cell lymphoma is unprecedented, but unfortunately it doesn’t come without a cost. Grade 3 or greater cytokine release syndrome and neurotoxicity are reported in a significant fraction of patients, likely as a consequence of inflammatory cytokine hyper-production or direct CAR-T cell-mediated toxicity, and require intensive monitoring and a multidisciplinary management. To this point, ongoing research is aimed at improving CAR-T cells’ efficacy and safety by identifying new targets and/or combining them with immunomodulatory agents. One additional toxicity, which has yet been seldom addressed, is the financial one; a single CAR-T cell treatment may cost up to 475,000 USD (without considering other associated costs) and compares only relatively favorably to other cellular therapies such as autologous or allogeneic stem cell transplant.
Dr. Ramos concluded by highlighting how CAR-T cells have revolutionized, in short time, the treatment of patients with relapsed aggressive leukemias and lymphomas and how fast the research is moving. Multiple trials are in progress, trying to cure also other hematological malignancies through the use of CAR-T cells by targeting antigens such as BCMA in multiple myeloma or CD7 in T-cell lymphomas. Many people in the audience raised questions about the potential efficacy of CAR-T cells for patients with solid tumors, but Dr. Ramos recommended caution because of the lower antigenicity and the more pro-tumoral microenvironment typically observed in these malignancies.
Authored by Yazeed Sawalha, MD, Cleveland Clinic, Cleveland, Ohio, USA
Chimeric antigen receptors (CAR) combine the antigen binding portion of a monoclonal antibody with the signal activating machinery of a T cell, usually the intracellular domains of the zeta chain of the TCR/CD3 complex. First-generation CARs were designed with a single signaling domain (zeta chain) and showed very limited clinical benefit. Next generation CAR-T cells include other stimulatory domains such as CD28 (second generation) and CD28 + 4-1BB (third generation) and have shown greater in vivo expansion and persistence compared with first generation CAR-T cells. Second generation CD19 CAR-T cells have shown significant clinical efficacy in the treatment of acute lymphoblastic leukemia (complete response [CR] rates of 70-90%) and diffuse large B cell lymphoma (CR rates of ~ 50%). Clinical trials of CAR-T cells have established that adequate host lymphodepletion prior to CAR-T cell infusions is necessary (e.g. with cyclophosphamide and fludarabine). Emerging data show that different co-stimulatory domains (CD28 versus 4-1BB) may not be equivalent and that CAR may need to be expressed in specific T cell subsets (naïve versus experienced cells).
Toxicity associated with CD19 CAR-T cell therapy include cytokine release syndrome (CRS), neurotoxicity and agammaglobulinemia. CRS is caused by release of cytokines, most importantly IL-6, from both CAR-T cells and other host immune cells. Patients with CRS have sepsis-like presentation with culture-negative fever, hypotension, and respiratory distress. Ruling out infection and empiric treatment with antibiotics are key, as these patients are typically neutropenic following lymphodepleting chemotherapy. CRS management involves supportive care and tocilizumab in severe cases. The other important complication is neurotoxicity (CRES – CAR-T cell related encephalopathy syndrome). CRES presentation is nonspecific and ranges from confusion, aphasia, and seizures, with rare fatal events reported.
Future directions in CAR-T cell therapy include developing CAR-T cells that eliminate κ+ tumor cells and spare λ+ cells. These κ-targeted CAR-T cells spare the normal B cells expressing the nontargeted λ light chain and therefore could be associated with minimal impairment in humoral immunity. In addition, clinical trials of CAR-T cells targeting CD30+ malignancies (e.g anaplastic large cell lymphoma and Hodgkin lymphoma) are ongoing. Other potential antigens/targets for CAR-T cells beyond CD19 and CD30 include BCMA (multiple myeloma), CD5 (mantle cell lymphoma), and others.