Discussion
MPM, ovarian cancer, tumor, cancers, TRuC-based, hematological malignancies, cytopenias, mesothelioma
OVARIAN CANCER, TUMOR, CANCERS, DISEASE, HEMATOLOGICAL MALIGNANCIES, SOLID TUMORS, CYTOPENIAS, MESOTHELIOMA, REGRESSION
The results of our study demonstrate the safety and feasibility of administering gavo-cel, a first-in-class TRuC-targeting mesothelin, in patients with mesothelin-expressing solid tumors. To our knowledge, this is the first report of an engineered T cell therapy inducing clinical responses by leveraging the activation of the TCR complex in an HLA-unrestricted manner.This study is also noteworthy because, to our knowledge, gavo-cel is the first anti-mesothelin adoptive T cell therapy to show consistent objective radiologic responses and one of few studies to show tumor regression in patients with solid tumorsAs expected, the most frequently reported AEs in this study were cytopenias related to the administration of LD. The most frequent non-hematological AE was CRS, which was reported in 78% of patients, being grade 3 or higher in 25% of patients. However, gavo-cel at the RP2D (1 × 10A single gavo-cel infusion resulted in radiologic tumor regression in 93% of patients, and the ORR among patients with mesothelioma or ovarian cancer receiving gavo-cel after LD was 21% and 29%, respectively, as assessed by BIRC. This is significant given that the median number of prior therapies was five, including at least one line of standard ICI therapy in 87% of patients with MPM. Notably, objective responses were observed only in patients who received gavo-cel after LD, which led to T cell expansion and persistence in a dose-dependent fashion, and induction of cytokine secretion, thus highlighting the importance of the conditioning regimen.In addition to inducing radiological responses, gavo-cel appeared to prolong survival in a heavily pre-treated patient population. The PFS and OS in MPM were 5.6 months and 11.2 months, respectively. These results are encouraging, as patients with MPM who fail ICI therapy are typically treated with chemotherapy regimens. In the second-line setting, such approaches render an ORR lower than 10%, a PFS of ~3 months and an OS of ~10 monthsA potential limitation of gavo-cel therapy is the fact that responses, regardless of depth, were, in some cases, of limited duration. Antigen escape and T cell exhaustion have been invoked to explain disease relapse in patients with hematological malignancies receiving adoptive T cell therapiesOur data strongly support the development of TRuC-based cell therapies in patients with solid tumors as well as mesothelin as a target. Given the promising preliminary results reported here, a phase 2 study is underway to evaluate the efficacy of gavo-cel in mesothelin-expressing cancers, which will allow for repeat intravenous dosing and the combination with ICI therapy as strategies to promote greater gavo-cel exposure and to prevent exhaustion of the engineered T cells.