Chimeric Antigen Receptor Therapy Continues to Perform Well in Lymphoma Patients

A patient's T cells can be altered with the addition of chimeric antigen receptors so as to make them aggressively target cancer cells. This form of immunotherapy is one of the best attempted to date, and is producing impressive results in a variety of cancers, starting with leukemia and lymphoma. Here is another example of positive results in a form of lymphoma: the treatment eliminates cancer to produce remission (called "complete response" in the paper) for nearly half of the patients in the small study, as opposed to the one in ten achieved through prior therapies. As the list of side-effects in the paper make clear, however, while this is a considerable improvement there is a still a way to go yet in the production of better cancer therapies.

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) in the United States, accounting for approximately 30%-40% of all cases of NHL. Studies examining outcomes in patients with relapsed/refractory DLBCL show that the response rates to subsequent therapy varies from 14% to 63%. However, relapsed/refractory DLBCL is broadly defined and consists of a heterogeneous patient population. Outcomes are particularly poor in those patients with truly refractory DLBCL, defined as no response to last line of chemotherapy or relapse within 1 year of autologous stem cell transplant (ASCT). A large patient-level meta-analysis of patients with refractory DLBCL found that outcomes in this homogeneous population are significantly worse, with a complete response (CR) rate of 8%, a partial response (PR) rate of 18%, and median overall survival of 6.6 months, indicating a major unmet need for effective therapies for these patients.

Adoptive cell therapy with T cells genetically engineered to express chimeric antigen receptor (CAR) targeting CD19 is a promising approach for treatment of B cell malignancies. A recent single-institution study demonstrated high response rates with an overall response rate of 73% and a CR rate of 55% with anti-CD19 CAR T cells containing CD3ζ/CD28 signaling domains administered in conjunction with low-dose cyclophosphamide conditioning regimen in patients with relapsed/refractory B cell lymphomas. KTE-C19 is an autologous CD3ζ/CD28-based anti-CD19 CAR T cell product that uses the same CAR construct as in the earlier study but is manufactured in a centralized, closed, and streamlined process of approximately 8 days. ZUMA-1 is the first multicenter study evaluating the safety and efficacy of anti-CD19 CAR T cells in patients with refractory NHL. We report here the safety, efficacy, and correlative studies of apheresis product, KTE-C19, and in vivo effects from the phase 1 portion of ZUMA-1.

As of August 2016, the median follow-up time was 9 months. Nine patients were enrolled in the study. Two patients experienced adverse events due to disease progression, discontinued the study, and never received KTE-C19. Seven patients received conditioning chemotherapy and KTE-C19. Patients ranged from 29 to 69 years of age and had received two to four prior lines of therapy. Three were refractory to second-line or later lines of therapy, and four patients had relapsed post-ASCT within 1 year. Despite the small numbers in this study, the overall and complete response (CR) rates were high and durable relative to historical controls. Durable efficacy of the KTE-C19 regimen was observed in patients with rigorously defined chemotherapy refractory disease who had no viable treatment options. Rapid CRs were demonstrated after only 1 month of follow-up in only those four (57%) patients who relapsed after prior ASCT, and responses are ongoing at 12+ months in three of seven (43%) patients. In these three patients, the duration of response with KTE-C19 markedly exceeded the time to relapse after their prior ASCT. This is remarkable, as the expected CR rate in this chemotherapy refractory patient population is 8%, and median survival is 6.6 months with conventional therapies.



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