Improving CAR-T Cell Therapy, One T Cell at a Time

A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 in Combination with Atezolizumab in Subjects with Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

NCT02926833

Kite Pharma, Inc.

City of Hope, Duarte, CA; Stanford Cancer Institute, Stanford, CA; H. Lee Moffitt Cancer Center, Tampa, FL; Dana-Farber Cancer Institute, Boston, MA; University of Texas MD Anderson Cancer Center, Houston, TX

This is an open-label phase I/II study investigating the safety and efficacy of chimeric antigen receptor (CAR) -T cell therapy with KTE-C19 in combination with the anti–PD-L1 antibody atezolizumab in patients with refractory diffuse large B cell lymphoma (DLBCL). All patients receive four doses of atezolizumab once every three weeks after their KTE-C19 infusion. In the phase I portion, however, there are three safety cohorts that differ with respect to the timing of the first dose of atezolizumab: cohort 1 at three weeks following KTE-C19, cohort 2 at two weeks following KTE-C19, and cohort 3 at one day following KTE-C19. Enrollment in each cohort will follow a 3 × 3 design, and patients will be observed for a dose-limiting toxicity (DLT) window of three weeks following the first atezolizumab dose. Following a safety review at the completion of the phase I portion, a phase II dosing schedule will be decided on, and up to 22 additional patients will be enrolled. Eligible patients include patients with DLBCL that is refractory to first-line, or their most recent line, of chemotherapy, or those who have relapsed within 12 months of autologous stem cell transplantation. The primary objective of this study is to determine the safety of KTE-C19 in combination with atezolizumab, as well as efficacy as measured by the complete response rate. Secondary objectives include measures of efficacy and tolerability, as well as biomarker and pharmacokinetic analyses.

Anti-CD19–directed CAR-T cell therapy was first evaluated in CD19⁺ B cell malignancies including B cell acute lymphoblastic leukemia (B-ALL), chronic lymphocytic leukemia, and B cell non-Hodgkin lymphoma five to 10 years ago; and the results have been dramatic. In pediatric and young adult B-ALL, the complete response rate is more than 80 percent, with almost two-thirds of patients in an ongoing remission at 12-month follow-up.¹  In adults with relapsed/refractory DLBCL, the response rates are approximately 60 to 80 percent, with complete responses seen in 40 to 70 percent of patients.^2,3  Following KTE-C19, 40 percent of patients maintain their complete response at six-month follow-up.²  Despite these impressive results, some patients do not respond at all, and some patients are destined to relapse following an initial response. The nature of both innate and acquired resistance is largely unknown. It has been shown, however, that CAR-T cells upregulate markers of T cell activation as well as immunomodulatory markers on their surface upon tumor antigen target engagement, including PD-1, which can lead to T cell exhaustion.⁴  In animal models, the use of anti–PD-1 antibodies enhances the activity of antitumor CAR-T cells, and this increase in activity has been associated with a decrease in myeloid-derived suppressor cells in the tumor microenvironment.^4,5  In DLBCL in particular, PD-L1 is expressed on some higher-risk lymphomas as well as in the tumor microenvironment, and blocking PD-1 has led to meaningful responses in a subset of DLBCL patients.^6,7  Combining CAR-T cell therapy with immune checkpoint blockade therapy targeting the PD-1/PD-L1 interaction could thus improve efficacy and overcome resistance following engineered T cell therapy for cancer patients in general and for DLBCL more specifically.

With the recent and anticipated U.S. Food and Drug Administration approvals of anti-CD19–directed CAR T cells in pediatric and young adult B-ALL and relapsed/refractory DLBCL, there is much enthusiasm and excitement about these therapies. More needs to be done, however, to understand the mechanisms of resistance so the efficacy of this therapy can be maximally achieved. Targeting the PD-1/PD-L1 axis may mark the first step in improving outcomes in a subset of patients. There has been at least one published case report of a patient with progressive DLBCL following anti-CD19–directed CAR-T cell therapy who was treated with an anti–PD-1 antibody and responded favorably.⁸  This response was associated with an expansion of CAR-T cells with decreased levels of PD-1 on their surface. The use of anti–PD-1 antibody therapy for relapsed or refractory DLBCL following CAR-T cell therapy is now being tested formally in a clinical trial (NCT02650999).

The study outlined here combines KTE-C19 with atezolizumab and is the first such study in DLBCL to administer the two therapies simultaneously. While the hope is that this combination will enhance CAR-T cell activity by improving both the expansion and persistence of CAR-T cells, the concern, of course, is for additional toxicity. Anti-CD19–directed CAR-T cell trials have a unique and potentially high-risk toxicity profile, with as much as 10 to 20 percent of patients experiencing at least grade 3 cytokine release syndrome (CRS) and up to 15 to 30 percent experiencing higher than grade 3 neurotoxicity in trials in DLBCL.^2,3  In rare cases, these toxicities have been fatal. It is plausible that adding PD-1 blockade to the mix might increase the rate of high grade CRS and neurotoxicity, and make them more difficult to treat. There has been at least one other trial, however, exploring this simultaneous combination in patients with neuroblastoma.⁹  Although this trial demonstrated that this combination was safe, it was not associated with enhanced expansion or persistence of CAR-T cells in this setting.⁹  Furthermore, the benefit of combining PD-1 blockade with CAR T cell therapy may be limited depending on the mechanism of resistance. Tumors that acquire resistance to anti-CD19 CAR-T cells by alternative splicing of CD19 such that tumor cells fail to trigger T cell killing are unlikely to be affected by the addition of such therapies.¹⁰  Trials such as these are among the first steps in trying to enhance CAR-T cell activity across both hematologic and solid tumor malignancies; however, uncovering mechanisms of escape will be vital to developing rational combination strategies and novel ways to combat resistance.