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MO09 - Mesothelioma I (ID 120)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Presentations: 1
- Moderators:K. Suzuki, S.G. Armato III
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 204 A+B, Level 2
MO09.03 - A pilot and feasibility trial evaluating two different chemotherapy regimens in combination with intrapleural adenoviral-mediated interferon-alpha (SCH 721015, Ad.hIFN-alpha2b) gene transfer for malignant pleural mesothelioma (ID 3374)
16:15 - 17:45 | Author(s): E.K. Moon
Malignant pleural mesothelioma is an incurable thoracic neoplasm for which combination chemotherapy offers limited improvement in survival. Novel agents that offer synergy with standard systemic cytotoxic therapy are under investigation. Among these agents are a variety of immunotherapeutics which can be administered either locally or in a systemic fashion.
We conducted a Phase I/II “in situ vaccination” clinical trial commencing in March2011 involving repeated intrapleural administration of a replication-defective recombinant adenoviral vector containing the human interferon-alpha (hIFN-α2b) gene at a dose of 3x10[11 ]viral particles concomitant with a 14-day course of high-dose cyclo-oxygenase-2 (COX-2) inhibitor (Celecoxib). This was followed by standard first-line or second-line chemotherapy agents. Primary outcome measures were safety, overall best response rate, and survival.
We completed accrual (n=25) in the first-line chemotherapy arm, in which all patients received pemetrexed-based chemotherapy regimens. This group included patients who previously received pemetrexed chemotherapy but did not subsequently receive this agent for >6 months. In the second-line chemotherapy arm, 13of a planned 15 subjects have enrolled (with 12 evaluable), all of whom received gemcitabine-based chemotherapy (Table 1). In both arms, the combination of intrapleural Ad.IFN-α2b vector, high-dose celecoxib, and systemic chemotherapy proved safe. Adverse events during the chemotherapy portion of the study were comparable to historical controls.Most patients experienced expected mild toxicities from vector (cytokine release syndrome, interferon production), including nausea, fatigue, anemia, lymphopenia (grade 3-4) and hypoalbuminemia. Serious adverse events included: pleural catheter infection (n=2); hypoxia (n=2); supraventricular tachycardia (n=1); and esophagitis (n=1), none directly attributable to the vector or vector administration. Serial chest CT and PET/CT scans demonstrated an overall response rate of 31% by Modified RECIST criteria and disease control rate (DCR) of 78% (partial and complete responses plus stable disease) at initial follow-up scan after the first two cycles of chemotherapy. Partial responses were seen in 9/25 evaluable patients with pemetrexed-based chemotherapy and 1/12 with gemcitabine. Patients who received first-line pemetrexed-based chemotherapy (n=14) had a median survival of 10.5 months, 95% ci=(5.5,inf), whereas second-line patients (n=21; 12 gemcitabine)had a median survival of 15.0 months, 95% ci=(9.0,inf).
Pem/Platin (N=25) Gemcitabine (N=13) Male % 64% (16/25) 84.6% (11/13) Median Age 67 (51-86) 65 (43-81) Histologic Subtype % Epithelioid - 17 (68%) Biphasic - 4 (17%) Sarcomatoid - 4 (17%) Epithelioid - 11 (84.6%) Biphasic - 2 (15.4%) Sarcomatoid - 0 Stage I - 2 (8%) II - 6 (24%) III - 13 (52%) IV - 4 (16%) III - 4 (30%) IV - 9 (70%) Prior Treatment Chemotherapy - 4 (16%) RP/PDT - 4 (16%) XRT - 5 (20%) Chemotherapy - 13 (100%) RP/PDT - 7 (53%) XRT - 2 (15%) Platin Agent Cisplatin - 12 Carboplatin - 10 Cis-Carbo - 1 None - 2 Cisplatin - 0 Carboplatin - 2 None - 8 Median Cycles of Chemo 6 (1-6) 3 (0-6)
The combination of intrapleural Ad.IFN-α2b vector, Celecoxib, and systemic chemotherapy proved safe. Disease control rates observed in this study compare favorably with historical data andthe especially encouraging OS in the second-line chemotherapy group argue strongly for proceeding with a multi-center randomized clinical trial of chemo-immunogene therapy versus chemotherapy alone.
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P3.14 - Poster Session 3 - Mesothelioma (ID 197)
- Event: WCLC 2013
- Type: Poster Session
- Track: Mesothelioma
- Presentations: 1
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
P3.14-007 - Chimeric Antibody Receptor (CAR) Augmented Adoptive T Cell Therapy (ACT) for Patients with Progressive Malignant Pleural Mesothelioma (MPM) (ID 1870)
09:30 - 16:30 | Author(s): E.K. Moon
ACT using genetically modified T cells has shown great promise in different malignancies (eg melanoma, chronic lymphoid leukemia.) Our group has recently applied this technology by creating T cells that express a chimeric antibody receptor (CAR) that targets the highly expressed tumor antigen, mesothelin to treat malignant mesothelioma (MM), ovarian, and pancreatic cancer and has initiated a Phase I trial in MM patients using mRNA transfected CAR T cells against mesothelin (CART-meso cells) to test its feasibility and safety.
Three patients with progressive MPM with epithelial or biphasic MPM underwent apheresis for T cell isolation/electroporation/expansion. To mitigate concerns about potential off-target toxicity due to low levels of mesothelin expression in normal tissues we developed “biodegradable” mesothelin-specific CAR engineered T cells that transiently express CAR transcripts following mRNA electroporation. T cells were electroporated with the CAR mRNA and then frozen aliquots were thawed and administered to the patients. Serum/peripheral blood/marrow mononuclear cells were acquired from patients during the trial to detect/quantify abundance of transgene and CD3e transcripts, soluble cytokine factors, human anti-mouse antibody (HAMA), CAR T cell-induced humoral responses against tumor antigens.
Adoptive transfer of mRNA engineered to express “biodegradable” CAR that target mesothelin was feasible. CARTmeso cells were detected in the blood and demonstrated the predicted transience of persistence in peripheral blood. Infusions were safe from the perspective of off target toxicity due to low level mesothelin expression in normal tissues. However, in one patient who received two courses of T cells, with the second course after a 6 week delay developed an anaphylactic reaction after T cell infusion, presumably due to IgE antibodies generated against the murine single chain antibody that is part of the CAR. We observed clinical activity in one patient who showed a 50% reduction in mediastinal tumor volume (Figure 1). This patient also developed antibodies against other proteins present in mesothelioma cell lines. Figure 1 Fig 1. Greater than 50% reduction in volume of mediastinal MPM tumor in one patient after infusion.
ACT of mRNA engineered CART-meso cells is feasible and safe from the perspective of off target toxicity due to low level mesothelin expression in normal tissues. mRNA engineered T cells can be used to evaluate potential issues of off-target CAR-mediated toxicity and support the development of CAR-based strategies to target mesothelin.