2511 Background: We conducted a phase I dose escalation trial of first-in-human autologous chimeric antigen receptor (CAR) T-cell immunotherapy targeting mesothelin (MSLN), a cell-surface antigen that is highly expressed in pleural cancers- malignant pleural mesothelioma (MPM) and metastatic lung and breast cancers. Methods: A single dose of CD28-costimulated MSLN CAR T cells with the I-caspase-9 safety gene was administered intrapleurally in patients with MSLN-expressing pleural tumors. Following a 3+3 design, patients were treated in dose escalating cohorts (dose range 3E5 to 1E7 CAR T cells/kg) following IV cyclophosphamide lymphodepletion (first 3 patients did not receive cyclophosphamide). A subset of MPM patients received subsequent anti-PD-1 therapy, off-protocol, which we have shown to prolong CAR T-cell functional persistence in preclinical models. Results: Twenty patients (18 MPM, 1 lung cancer, 1 breast cancer) were treated (prior lines of therapy 1–8, 35% received ≥3 lines of therapy). No CAR T-cell–related toxicities higher than grade 1 were observed. 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 EKG evaluation found no evidence of toxicity. Fourteen MPM patients received subsequent anti-PD1 therapy (1–21 cycles, pretreatment tumor PD-L1 < 10% in all patients except one), with 1 patient developing grade 3 pneumonitis that responded to steroid treatment. CAR T cells were detected in the peripheral blood of 13 of 14 patients (1-39 weeks). At data cut-off date (Jan 31, 2019), among 14 MPM patients that received combination therapy (follow-up 13-77 weeks, median 31 weeks), best responses included 2 patients with complete metabolic response on PET (62 and 39 weeks ongoing); 5 partial responses and 4 stable disease by investigator assessment. Conclusions: Intrapleurally administered MSLN-targeted CAR T cells were safe. Encouraging antitumor activity of MSLN-targeted CAR T-cell therapy was observed when combined with anti-PD1 therapy and shows promise for future development of this approach. Clinical trial information: NCT02414269.
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.
How does craving bias decisions to pursue drugs over other valuable, and healthier, alternatives in addiction? To address this question, we measured the in-the-moment economic decisions of people with opioid use disorder as they experienced craving, shortly after receiving their scheduled opioid maintenance medication and ~24 h later. We found that higher cravers had higher drug-related valuation, and that moments of higher craving within-person also led to higher drug-related valuation. When experiencing increased opioid craving, participants were willing to pay more for personalized consumer items and foods more closely related to their drug use, but not for alternative “nondrug-related” but equally desirable options. This selective increase in value with craving was greater when the drug-related options were offered in higher quantities and was separable from the effects of other fluctuating psychological states like negative mood. These findings suggest that craving narrows and focuses economic motivation toward the object of craving by selectively and multiplicatively amplifying perceived value along a “drug relatedness” dimension.
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