RESUMO
Relapse after CD19-directed chimeric antigen receptor (CAR)-modified T-cells remains a substantial challenge. Short CAR T-cell persistence contributes to relapse risk, necessitating novel approaches to prolong durability. CAR T-cell reinfusion (CARTr) represents a potential strategy to reduce the risk of, or treat, relapsed disease after initial CAR infusion (CARTi). We conducted a retrospective review of reinfusion of murine (CTL019) or humanized (huCART19) anti-CD19.4-1BB CAR T-cells across 3 clinical trials or commercial tisagenlecleucel for relapse prevention [peripheral B-cell recovery (BCR) or bone marrow hematogones ≤6 months after CARTi], minimal residual disease (MRD) or relapse, or nonresponse to CARTi. The primary endpoint was complete response (CR) at day 28 after CARTr, defined as complete remission with B-cell aplasia. Of 262 primary treatments, 81 were followed by ≥1 reinfusion (investigational CTL019, n=44; huCART19, n=26; tisagenlecleucel, n=11), representing 79 unique patients. Of 63 reinfusions for relapse prevention, 52% achieved CR (BCR, 15/40, 38%; hematogones, 18/23, 78%). Lymphodepletion was associated with response to CARTr for BCR (OR 33.57, P = 0.015), but not hematogones (OR 0.30, P = 0.291). The cumulative incidence of relapse was 29% at 24-months for CR versus 61% for nonresponse to CARTr (P=0.259). For MRD/relapse, CR rate to CARTr was 50% (5/10), but 0/8 for nonresponse to CARTi. Toxicity was generally mild, with the only grade ≥3 cytokine release syndrome (n=6) or neurotoxicity (n=1) observed in MRD/relapse treatment. Reinfusion of CTL019/tisagenlecleucel or huCART19 is safe, may reduce relapse risk in a subset of patients, and can reinduce remission in CD19-positive relapse.
RESUMO
Translational data on chimeric antigen receptor (CAR) T-cell trials indicate that the presence of naïve T cells in the premanufacture product is important to clinical response and persistence. In anticipation of developing CAR trials for other tumors, we investigated the T-cell distribution from children with solid tumors and lymphomas at diagnosis and after every cycle of chemotherapy. We found that patients with T cells enriched for naïve and stem central memory cells expanded well in vitro, but the majority of tumor types showed chemotherapy-related depletion of early lineage cells with a corresponding decline in successful ex vivo stimulation response. Unexpectedly, many pediatric patients with solid tumors had low numbers of naïve T cells prior to any therapy. These data indicate the ex vivo manufacture of CAR T cells may need to be customized based on the nature of T cells available in each disease type. SIGNIFICANCE: Cumulative chemotherapy cycles deplete naïve T cells in many pediatric cancer regimens, reducing expansion potential associated with successful adoptive cellular therapies. Naïve T-cell deficits can be seen at diagnosis as well, implying immune deficits that exist prior to chemotherapy, which may also affect the development of immune-based therapies.See related commentary by Leick and Maus, p. 466.This article is highlighted in the In This Issue feature, p. 453.
