Kenderian, Saad Sirop

Key Points The risk of transformation of NLPHL to DLBCL is 0.74 per 100 patient-years of follow-up. Risk factors for transformation include prior exposure to chemotherapy and splenic involvement at time of diagnosis.

Abstract Purpose: Responses to therapy with chimeric antigen receptor T cells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle cell lymphoma (MCL) represents a B-cell malignancy that remains incurable despite novel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019 therapy are scant. Using MCL as a model, we sought to build upon the outcomes from CTL019 and from ibrutinib therapy by combining these in a rational manner. Experimental Design: MCL cell lines and primary MCL samples were combined with autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of the combination was studied in vitro and in mouse xenograft models. Results: MCL cells strongly activated multiple CTL019 effector functions, and MCL killing by CTL019 was further enhanced in the presence of ibrutinib. In a xenograft MCL model, we showed superior disease control in the CTL019- as compared with ibrutinib-treated mice (median survival not reached vs. 95 days, P < 0.005) but most mice receiving CTL019 monotherapy eventually relapsed. Therefore, we added ibrutinib to CTL019 and showed that 80% to 100% of mice in the CTL019 + ibrutinib arm and 0% to 20% of mice in the CTL019 arm, respectively, remained in long-term remission (P < 0.05). Conclusions: Combining CTL019 with ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients with MCL and other types of B-cell lymphoma. Clin Cancer Res; 22(11); 2684–96. ©2016 AACR.

Abstract Several decades of humoral immunotherapy using monoclonal antibodies and cellular immunotherapy using hematopoietic cell transplantation have recently culminated in a successful merger: the development and clinical application of genetically engineered antibody–T cell chimeras. Also known as chimeric antigen receptor T cells (CAR T cells), these entities combine the exquisite antigen specificity of antibodies with the polyfunctionality and potency of cellular immunity and are a prime example of the potential for synthetic biology to treat disease. CAR T cells overcome several of the biologic obstacles that have historically hampered immunotherapy while providing fundamental mechanistic insights into cellular immunology and revealing new challenges in genetic engineering and target selection. Results from early-phase CAR T-cell–based clinical trials demonstrate the significant potential for this approach to affect dramatic and complete clinical responses while revealing novel toxicities associated with activation of potent and specific antitumor immunity. Cancer Res; 74(22); 6383–9. ©2014 AACR.