ONCAlert | Upfront Therapy for mRCC

For Advanced Heme Malignancies, CAR T Cells Overcome Exhaustion, Tumor Escape

Jennifer Gray Tomilov, PhD
Published Online: Dec 27,2019
Progress in the development of chimeric antigen receptor (CAR) T-cell therapy and other cell-based therapies has led to new therapeutic options for advanced malignancies. CAR T-cell agents approved by the FDA in recent years include axicabtagene ciloleucel (Yescarta) for diffuse large B-cell lymphoma (DLBCL) and tisagenlecleucel (Kymriah) for both DLBCL and acute lymphoblastic leukemia (ALL). Approval of the CD19-specific axicabtagene ciloleucel was based on a single-arm, multicenter trial evaluating 101 adult patients with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma.1 The objective response rate (ORR) after treatment was 72%, and the complete remission (CR) rate was 51%. Patients with CR did not reach an estimated duration of response (DOR) after a median follow-up of 7.9 months, whereas patients with partial remission (PR) reached an estimated median DOR of 2.1 months.

The phase II JULIET trial evaluated the CD19-directed autologous T-cell immunotherapy tisagenlecleucel in patients with R/R DLBCL and DLBCL after transformation from follicular lymphoma.2 The ORR in this study was 50%, and the CR rate was 32%. The estimated median response duration for patients with a PR was 3.4 months, but the DOR was not reached in patients achieving CR at a median follow-up of 9.4 months. Approval of tisagenlecleucel for B cell precursor ALL followed a study including patients with R/R pediatric precursor B-cell ALL. The confirmed overall remission rate was 82.5%, wherein 63% of patients achieved CR and 19% had CR with incomplete hematological recovery.3 The median remission duration was not reached in this study (range, 1.2-14.1+ months).

Advances in CAR T-Cell Therapies: Combating Tumor Escape and T-Cell Exhaustion

Although CD19-directed CAR T-cell therapies have shown initial efficacy in R/R hematologic malignancies, not all patients respond to this therapy, and long-term disease control is challenging because of the prevalence of CD19-neg-ative immune escape.4 To address this issue, development of CAR T cells targeting the CD22 antigen is under way. Results from a recent phase I, first-in-human trial indicated the safety and efficacy of a CD22-targeted CAR (CD22-CAR) therapy in 21 children and adults with R/R B-ALL, including 17 patients previously treated with CD19-directed immunotherapy. All patients had received at least 1 prior hematopoietic stem cell transplantation (HSCT), and 2 had received prior HSCT twice.5 Dosing was administered according to a standard 3 + 3 phase I dose-escalation design.

Dose-dependent anti-leukemic activity was observed, and CR was obtained in 11 of the 15 patients (73%) receiving ≥1 × _106 CD22-CAR T cells per kilogram of body weight, including 9 of 10 patients who had received prior CD19-directed immunotherapy and 5 of 5 patients with CD19-diminished or CD19-negative B-ALL.5

Median remission duration was 6 months. The primary adverse event (AE) was cytokine release syndrome, which occurred in 16 of 21 patients.

Despite clinical activity of CD22-CAR T cells in B-ALL and leukemia resistant to anti-CD19 immunotherapy, relapses were associated with diminished CD22 site density, which likely pro-moted tumor cell escape from killing by CD22- CAR T cells.5 Specifically, of the 12 patients who obtained a CR, 3 remained in CR after 21, 9, and 6 months, but 8 patients relapsed after 1.5 to 12 months.

T-cell exhaustion is also being studied as a mechanism underlying CAR T cell therapy relapse.

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For Advanced Heme Malignancies, CAR T Cells Overcome Exhaustion, Tumor Escape
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