Bhagirathbhai Dholaria, MD, from Vanderbilt University, reports from the 2022 West Oncology Conference - Updates for Advanced Practitioners and Nurses.
Chimeric Antigen Receptor T-cells, also known as CAR-T cells, are emerging as a viable treatment option for many cancers, particularly lymphomas. At the 2022 West Oncology Conference for Nurses and Advanced Patient Practitioners (APPs), Dr Bhagirathbhai Dholaria reviewed the key features of this cutting-edge technology, and described its application in the setting of lymphoma treatment.
A Case in Point
Dr Dholaria described a case from his own practice of a patient with diffuse, large B-cell lymphoma (DLBCL) in which the patient was treated with the standard “chemo-immunotherapy” regimen consisting of rituximab (R), an immune cell-targeting antibody, combined with the standard chemotherapy backbone known as CHOP (R-CHOP). For a patient such as this, he noted R-CHOP would be a standard first-line regimen, and most patients will respond very well and achieve disease remission. For some patients, however, an early relapse (in this case, within 6 months) will occur, and in such patients, the options are so-called ‘salvage’, or rescue chemoimmunotherapy (to achieve disease control), followed by high dose chemotherapy and an autologous stem cell transplant (ASCT). Despite this option, however, the number of patients who are actual candidates for ASCT is small, and many patients do not survive long enough, do not respond to salvage therapy, are too old, or have too many comorbid conditions to undergo transplant. For example, in the SCHOLAR study of patients with relapsed or refractory (R/R) DLBCL, the median response to next-line therapy was only 26%, median overall survival (OS) was only 6.3 months, and 2-year OS was only 20%. In the face of these dismal outcomes for R/R DLBCL, Dr Dholaria noted that the availability of CAR-T cell therapy has now provided another treatment option for patients.
About CAR-T Cells
CAR-T cells, simply put, are the patient’s own T-lymphocytes which are harvested from their blood and genetically engineered, outside of the body (“ex-vivo”), to express a T-cell receptor molecule that is specifically designed to recognize and target a surface antigen on the cancer cells – in the case of lymphoma, a molecule called CD19. As such, when re-introduced into the patient’s body, the CAR-T cells will find, and selectively kill the cancer cells, without harming normal cells. An advantage of CAR-T cells is that they can effectively harness two arms of the patient’s own immune system; cytotoxic T-cells which can efficiently kill the CD19-expressing cancer cells, and T-cell memory, whereby the patient’s immune cells can recognize and ‘remember’ the cancer cells if they should come back again. Dr Dholaria also noted the technological advances in CAR-T cell development over time; whereas the first generation of CAR-T cells were largely ineffective, and responses were generally short-lived, second-generation CAR-T cells last longer and perform better when re-introduced into the patient, and now 3rd, 4th, or even 5th generation CAR-T cell preparations are now being developed which can further overcome these limitations and improve efficacy.
Compelling Data in Lymphoma
Data from clinical trials such as ZUMA-1 (axi-cel preparation), JULIET (Tisa-cel preparation) and TRANSCEND (liso-cel preparation) have demonstrated the efficacy of anti-CD19 CAR-T cells in R/R DLBCL, such that some 40% of patients can now achieve durable remissions with no further therapy. In the case of R/R DLBCL which Dr Dholaria described, for example, the patient received axi-cel and has achieved remission for nearly 2 years of follow up. In the second line setting, Dr Dholaria also described clinical trial results showing a significant benefit of axi-cel in event-free survival (EFS) as compared with the standard of care (SOC) of salvage chemotherapy followed by ASCT for patients with primary refractory disease, or those with an early relapse (within 12 months). While there was no benefit in overall survival between the arms in this study, this was largely due to the fact that patients who did not respond to the salvage chemotherapy on SOC were offered the option to cross over to CAR-T cell therapy. As such, the treatment is now approved by the US Food and Drug Administration (FDA) as a second line therapy in this setting. Additional clinical trial results have also added a second CAR-T preparation, liso-cel, as an option for these patients. Dr Dholaria also reviewed some data for patients with R/R B-cell acute lymphoblastic leukemia (ALL) showing rates of complete remission of over 70% for patients on the tisa-cel preparation.
The Pitfalls of CAR-T Cells
The principal toxicities associated with CAR-T cell therapy are related to the release of inflammatory mediators termed cytokines, by the activated T-cells when they are re-infused into the patient. These mediators can result in a systemic inflammatory response termed cytokine release syndrome (CRS), which occurs in about 80% of patients, and because they can also pass into the brain and nervous system, and they may also cause neurotoxicity. These events are typically seen within 7 to 14 days following the CAR-T infusion and resolve by week 3 or 4 in most cases. There are treatments available to block the impact of CRS, including, in milder cases, drugs such as Tylenol (acetaminophen), but also tocilizumab (an antibody directed against the inflammatory mediator interleukin 6), and high-dose steroids. Reduction in blood cells counts (anemias or cytopenias), may also occur with CAR-T cells, but can generally be managed with supportive care measures, transfusions, or additional growth factor therapies. Other complications that have been associated with CAR-T cell therapy such as B-cell aplasia may require measures such as antibiotics or immunoglobulin therapy. Protocols such as prophylactic steroid use in the initial period after CAR-T cell infusion can also help to reduce the incidence of high-grade CRS or neurotoxicity, and Dr Dholaria noted this is now standard practice at his institution for patients undergoing CAR-T cell therapy.
Another consideration when evaluating whether patients are candidates for CAR-T cell therapy is whether their disease is stable enough and/or if they will require bridging therapy to control their disease while the CAR-T cells are being manufactured, a process which typically takes between 3 and 8 weeks. Patients should need to have adequate organ function and blood cell counts, and be able to tolerate the lymphodepletion therapy that is needed to undergo CAR-T therapy. In addition, there may be cost or insurance coverage issues to consider which could limit access for some patients.
In summary, Dr Dholaria noted that CAR-T technology represents an exciting new therapy for patients with lymphoma, and all patients with hematologic malignancies should be considered for CAR-T cell therapy, whether in a commercial or clinical trial setting. While some toxicities and logistical challenges remain, he expects that with advanced technologies such as anti-cytokine therapies to control CRS, and/or improved formulations, CAR-T cell therapy should become safer, more effective, and more accessible to patients in the near future.
See more from the 2022 West Oncology APP here.
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