Discussion
heterogenous, cancers, tumor, fever, impaired bone marrow function, toxicity, cancer, non-tumor, TEAEs, CRS, cytopenia, HLH, hematotoxicity
CANCERS, TUMOR, CANCER, HEMATOLOGICAL MALIGNANCIES, DISEASE, SOLID TUMORS, RECRUITMENT, CYTOPENIA, BONE MARROW SUPPRESSION, SEQUELAE
Extending the success of CAR-T cells to solid tumors presents significant hurdles, primarily due to the scarcity of distinct, tumor-specific targets, complicating the development of efficacious CAR-T therapies for these cancers. Notwithstanding these obstacles, several early-phase clinical trials are underway targeting molecules including mesothelin, Muc16, Folate receptor and carcinoembryonic antigenThe effectiveness and safety of CAR-T cell therapy largely hinges on on-target specificity. Targeting antigens such as her2neu, GD2 and CLDN18.2 that are also expressed by non-tumor tissue could lead to on-target, off-tumor toxicity where the antigen in healthy tissue is accessible to CAR-T cellsTo our knowledge, this is the first report on the clinical performance of CAR-T cells directed against CLDN6, an oncofetal antigen with no detectable CLDN6 expression in healthy adult human tissuesThe addition of the RNA-LPX-based CARVac at doses determined in previous trials did not alter the safety profile of CLDN6 CAR-T cells substantially.The TEAEs we observed (for example, CRS and one case each of HLH (G4) and ICANS (G1)) have been reported for CAR-T cell products used in hematological malignancies, and are most likely associated with this treatment modality. CRS was mostly G1–2, well manageable and resolved without sequelae.Other TEAEs ≥G3 were hematological ones, for example, cytopenia. GCT patients with impaired bone marrow function due to recent prior intensive myelosuppressive treatment were found to be especially at risk for treatment-related prolonged bone marrow suppression. Our observations indicate that omitting LD altogether may not be an option due to lack of CAR-T expansion without LD. To mitigate risks of enhanced hematotoxicity associated with prior treatments typical for the cancer types in this study, we continue to assess approaches such as dose-reduced LD protocols supported by CARVac-mediated CAR-T cell expansion. All reported safety-relevant findings (including asymptomatic transaminase/lipase elevations) had resolved by the time of this interim analysis.Overall, the study supports CLDN6 as a safe target for cell therapy in solid tumors and does not raise concerns for either combining CAR-T cells with CARVac or for exploring higher doses of CLDN6 CAR-T cells. Given that CARVac dosing improved engraftment for patients treated at DL1 dosed with CARVac four days post-ACT but not for those at DL2 dosed following peak expansion (23–51 days post-ACT), future cohorts will be treated at the earlier time point regardless of the dosing level. With this trial being continued, the safety data set will be extended, allowing more detailed characterization of the preliminary observations we made in the first 22 patients.This interim analysis showed encouraging clinical activity of CLDN6 CAR-T cells with and without CARVac in a heterogenous set of patients. Enrolled patients were heavily pretreated, had active disease with r/r solid tumors, and the baseline CT scans were performed on average almost six weeks before ACT, altogether being conditions that may underestimate the potential clinical activity of CLDN6 CAR-T cells.In the higher DL of 1 × 10More than half of the patients suffered from GCT. Subgroup analysis of those GCT patients treated with 1 × 10The remaining nine enrolled patients were too heterogenous in terms of tumor types for indication-specific assessment of CAR-T cell activity. Of the three patients with EOC treated at the higher DL, two experienced an objective response warranting further exploration of this tumor type.An important finding was the robust engraftment and expansion of CLDN6 CAR-T cells after a single administration, which has been a limiting factor for a number of clinical trials of CAR-T cells in solid tumorsCARVac administration was well tolerated among trial participants, signifying its potential for combination therapy with CAR-T cells. Upon receiving CARVac, patients typically experienced a brief period of fever. Transient interferon-gamma release was observed post-CARVac administration indicating proper innate immune stimulation. In addition to these indicators of immune stimulation, we observed temporary increases in the frequency of CAR-T cells in some patients who received CARVac. While these preliminary findings indicate that CARVac may aid in boosting the expansion of CAR-T cells, potentially enhancing their therapeutic potency, the overall impact of CARVac on CAR-T cell pharmacokinetics is difficult to quantify based on the highly heterogeneous and small-sized set of patients analyzed. Given the importance of long-term persistence and robust expansion of CAR-T cells and motivated by these promising early findings, we continue to investigate the effects of higher doses of CARVac and assess the impact of repeated vaccine administration on prolonging persistence in this ongoing trial.As this study is a single arm trial with no comparator or control group, selection bias cannot be ruled out. The study is further limited by the small size, a relatively short follow-up duration with patients still on trial at the time of data cutoff, and by the all-comer nature of the trial, which resulted in recruitment of individual patients with distinct tumor indications, meaning that the suitability of these indications for treatment with CLDN6-directed CAR-T cells remains unclear. Treatment of more patients with standardized CARVac treatment algorithms are required to draw clear conclusions about the potential role of CARVac in supporting CAR-T cell engraftment and persistence.In conclusion, CLDN6 CAR-T cells resulted in robust engraftment, with a manageable safety profile and strong signals of clinical activity in patients with CLDN6-positive solid tumors with high unmet medical need. The encouraging response rates in these high medical need populations led us to develop an automated manufacturing process to scale up manufacturing, and we have initiated a repeat of dose escalation with this IMP, introducing further dose levels for both CAR-T cells and CARVac. Following identification of a recommended phase 2 dose, the trial will proceed to open expansion cohorts in select indications.