MD Anderson’s CAR/NK Therapy Shows Improved Safety Profile in B-Cell Malignancies
Investigators observed no notable toxicities including cytokine release syndrome, neurotoxicity or graft-versus-host disease.
Katy Rezvani, MD, PhD
Credit: MD Anderson
Investigators from MD Anderson found that CAR19/IL-15 CBU-NK (CAR19/IL-15) cells had a similar efficacy profile and an improved safety profile when compared with autologous CAR19 T cells in patients with CD19+ B cell malignancies.1
“The responses observed in these patients are very encouraging as we continue to evaluate the long-term efficacy of CAR NK cells in the treatment of these malignancies,” senior author Katy Rezvani, MD, PhD, professor, Stem Cell Transplantation & Cellular Therapy, MD Anderson, said in a statement.2 “In order to have a successful allogeneic cell therapy, it is also critical that we identify the characteristics of an optimal allogeneic donor for CAR NK manufacturing. We were able to identify two key factors associated with cord blood units most likely to yield a positive clinical response and discerned the biologic mechanisms underlying this phenomenon.”
Data from 37 patients in a phase 1/2 trial (NCT03056339) were published in Nature Medicine. Rezvani and colleagues found that CAR19/IL-15 was not associated with any notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease.
“Our study stresses the importance of identifying donor-specific predictors of response after allogeneic cell therapy, especially since one donor may be used to treat hundreds of patients. CAR NK cells have the potential to be manufactured in advance and stored for off-the-shelf immediate use,” Rezvani added.2 “This could potentially increase patient access to these cell therapies, reduce treatment time and lower cost of therapy.”
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Trial participants had an overall response (OR) rate of 48.6% at days 30 and 100, overall survival of 68% at 1 year, and progression-free survival of 32% at 1 year. Responders had higher levels and longer persistence of CAR-NK cells than nonresponders.
Specifically, responders included 100% of patients with low-grade non-Hodgkin lymphoma (NHL), 67% of patients with chronic lymphocytic leukemia (CLL) without transformation, and 41% of patients with diffuse large B-cell lymphoma (DLBCL). Most responses were complete responses (CR), with 83% of patients with NHL, 50% of patients with CLL, and 29% of patients with DLBCL achieving CRs. Two responders during the phase 1 portion received a stem cell transplant and no post-remission therapy was administered in the dose-expansion portion. Patients that achieved early remission had a 70% probability of remaining in CR at 1 year.
Investigators found that the most significant predictor for superior outcome was receiving CAR-NK cells from a cord blood unit (CBU) with at most 8 × 107 nucleated red blood cells and a collection-to-cryopreservation time of at most 24 hours. These NK cells were highly functional and enriched in effector-related genes compared with NK cells from suboptimal CBUs that had upregulation of inflammation, hypoxia and cellular stress programs. Furthermore, superior antitumor activity of CAR/IL-15 NK cells was confirmed using multiple mouse models in vivo.
“Moreover, our findings underscore the importance of defining the criteria for the selection of an allogeneic donor for CAR-NK cell production and identifying donor-specific predictors of response,” Rezvani and colleagues concluded in the paper.1
