Abstract CT036: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy

Abstract

Background: Malignant pleural disease (MPD) from primary malignant pleural mesothelioma (MPM) or secondary metastatic disease (lung and breast cancers) affects more than 150,000 patients a year in the US alone. We developed chimeric antigen receptors (CARs) to target mesothelin (MSLN), a cell-surface antigen that we have shown is highly expressed in MPD, is associated with aggressiveness and poor survival, and has low expression in normal tissues. Methods: Using a second-generation CD28-costimulated MSLN CAR with the Icaspase-9 safety gene (IcasM28z), we initiated a phase I clinical trial (NCT02414269) to determine the safety and maximum tolerated dose of intrapleurally administered CAR T cells. Patients with biopsy-proven MPD expressing MSLN were eligible for the study. A single dose of IcasM28z CAR T cells was administered intrapleurally (with or without cyclophosphamide preconditioning) by either pleural catheter or an interventional radiology procedure. On-target, off-tumor toxicity, serial serum soluble MSLN-related peptide (SMRP) levels and C-reactive protein levels were assessed, and CT and PET scans were performed, in addition to routine clinical and laboratory tests. Results: Twenty-one patients with MPD (19 MPM, 1 lung cancer, 1 breast cancer) were treated (40% received ≥3 lines of prior therapy). Eighteen of the 21 patients received cyclophosphamide preconditioning (3E5 - 1E7 CAR T cells/kg); the first cohort did not receive cyclophosphamide. Twelve patients were administered CAR T cells using an interventional radiology procedure. One patient had febrile neutropenia (grade 3) related to cyclophosphamide. No CAR T-cell-related toxicities higher than grade 2 were observed. The last cohorts of patients were admitted 2 weeks after infusion with a temperature of 101°F and fatigue. Intense monitoring for on-target, off-tumor toxicity by clinical (chest or abdominal pain), radiological (CT/PET or echocardiogram for pericardial effusion, ascites), laboratory (troponin elevation), and other (electrocardiogram) evaluation found no evidence of toxicity. One patient successfully underwent curative-intent surgical resection 6 weeks after CAR T-cell infusion. CAR T cells were detected in the peripheral blood of 13 patients (day 1 to 38 weeks), as evidenced by vector copy number. T-cell persistence was associated with decreased serum SMRP levels (>50% compared to pretreatment) and evidence of tumor regression on imaging studies. Once lack of toxicity had been established (6-17 weeks after CAR T-cell infusion), 14 patients received anti-PD1 checkpoint blockade agents (1-21 cycles), off protocol, with no toxicity. The best response among the 19 MPM patients (13 patients received anti-PD1 agent; PD-L1 <10% in all except 1) was - 2 patients had complete metabolic response on PET scan (60 and 32 weeks ongoing); 5 with partial response and 4 with stable disease. Conclusion: In this phase I clinical trial, intrapleurally administered MSLN-targeted CAR T cells had no evidence of on-target, off-tumor or therapy related toxicity, and there was evidence of CAR T-cell antitumor activity. MSLN-targeted CAR T-cell therapy combined with anti-PD1 agents shows encouraging clinical outcomes, thus a combination therapy trial is planned to recruit patients in the second quarter of 2019. Citation Format: Prasad S. Adusumilli, Marjorie G. Zauderer, Valerie W. Rusch, Roisin E. O'Cearbhaill, Amy Zhu, Daniel A. Ngai, Erin McGee, Navin K. Chintala, John C. Messinger, Alain Vincent, Elizabeth F. Halton, Claudia Diamonte, John Pineda, Shanu Modi, Stephen B. Solomon, David R. Jones, Renier J. Brentjens, Isabelle Rivière, Michel Sadelain. A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT036.

Cellular Immunotherapy and Locoregional Administration of CAR T-Cells in Malignant Pleural Mesothelioma

“…Moreover, the intra-pleural treatment dose was 30-fold lower than the intravenous administered dose and elicited no grade III/IV toxicities. In a clinical setting, no'on-target, off-tumor' effects were seen when 21 patients with malignant pleural disease were treated with CD28-costimulated MSLN CAR-T cells intrapleurally (85,90,91). In this study 19 out of 21 patients had MPM, of whom 13 were subsequently treated with pembrolizumab (anti-PD1).…”

“…In this study 19 out of 21 patients had MPM, of whom 13 were subsequently treated with pembrolizumab (anti-PD1). In total two patients had a CR, five had PR and four had SD as best overall response (85). Just as for DC therapy, Combining CAR Tcell therapy with anti-PD1 treatment showed promising clinical results.…”

CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

“…CAR T cells have been evaluated in early phase clinical studies for more than a decade, targeting a broad range of tumor antigens, including B7-H3, CAIX, CEACAM5, CD133, CD171, epidermal growth factor receptor (EGFR), EGFRvIII, FRa, GD2, GPC3, HER2, interleukin (IL)-13Ra2, mesothelin, MUC1, prostate-specific membrane antigen (PSMA), ROR1, and vascular endothelial growth factor (VEGF)-R2. 19,20,[22][23][24][25][26][71][72][73][74][75][76][77][78][79][80][81][82] Table 1 lists selected published studies, and Table 2 lists ongoing clinical studies. Early studies focused on first-generation CARs specific for CAIX, CD171, FRa, GD2, or IL-13Ra2.…”

“…[276][277][278] Checkpoint blockade/ CAR T cell therapy combinations are actively being pursued, 279 including the aforementioned clinical studies combining mesothelin-CAR T cells with pembrolizumab for the treatment of mesothelioma. 76 Furthermore, several studies have highlighted the benefit of combining radiotherapy with the administration of CAR T cells, and early clinical studies for patients with B cell lymphoma have produced encouraging results. 280 Recent preclinical studies have also demonstrated the benefit of boosting CAR T cells outside the immunosuppressive TME with amphiphile CAR ligands or RNA-based vaccines.…”

Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future

“…A phase I study (NCT02414269) drawing on preclinical results in orthotopic mouse MPM models (120,121) is ongoing to test the MSLN-CAR-T cells in multi-treated MPM patients. Preliminary results presented at the AACR [Abstract CT036, (122)] and ASCO [Abstract 2511, (123)] meetings this year have shown an ORR and DCR of 36.8 and 57.8%, respectively, in a cohort treated off protocol in combination with pembrolizumab.…”