The ongoing annual AACR meeting this week included some sort of encouraging (but far from final) news on using immunotherapy to counter mesothelioma and other awful tumors (pancreatic and ovarian tumors). The news is from an abstract for a paper focused on a research project using immunotherapy to treat tumors that express a protein known as mesothelin. The abstract is pasted below. In essence it says the safety issues are probably manageable and there are some small signs of possible efficacy.
The point of immunotherapy is to stop tumors from successfully “hiding” from the immune system. Once the immune system can “see” the tumors, it sometimes can mount a successful attack on the tumors. Some times the reaction is too much and produces a “cytokine storm” that can be fatal. However, researchers and physicians are learning how to avoid the storms usiing surgery to reduce the tumor bulk, and various other tools, including chemotherapies and steroids. For more specifics, see this April 2, 2014 open access article in Nature, by Heidi Ledford: “Cancer treatment: The killer within The immune system can be a powerful weapon against cancer — but researchers are still grappling with how to control it.”Abstract Number:CT105Presentation Title:Safety and feasibility of chimeric antigen receptor modified T cells directed against mesothelin (CART-meso) in patients with mesothelin expressing cancersPresentation Time:Sunday, Apr 19, 2015, 1:35 PM – 1:55 PMLocation:Terrace Ballroom I (400 Level), Pennsylvania Convention CenterAuthor Block:Janos L. Tanyi, Andrew R. Haas, Gregory L. Beatty, Mark A. Morgan, Caitlin J. Stashwick, Mark H. O’Hara, David L. Porter, Marcela V. Maus, Bruce L. Levine, Simon F. Lacey, Anne Marie Nelson, Maureen McGarvey, Naseem DS Kerr, Gabriela Plesa, Carl H. June. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PAAbstract Body:A phase I study to evaluate the safety and feasibility of an intravenous infusion of autologous T cells transduced to express a chimeric antigen receptor directed against mesothelin (CART-meso) in patients with mesothelin expressing tumors is being conducted at the University of Pennsylvania. Here we report on the first five patients treated with CART-meso T cell infusion. Five patients with recurrent advanced stage cancers (two serous ovarian, two epithelial mesothelioma, and one pancreatic) who had received 4-12 prior regimens, were treated with a single infusion of CART-meso cells. Apheresed autologous T cells were transduced with a lentiviral vector expressing the CAR construct composed of an extracellular anti-mesothelin single chain variable fragment derived from mouse monoclonal antibody (SS1) fused to the intracellular signaling domains of 4-1BB (CD137) and TCRzeta. Each patient received a single dose of 1-3 x 10^7 CART-meso cells/m2. No lymphodepletion with chemotherapy was given prior to infusion. All subjects enrolled were successfully infused and there were no acute adverse events (AE) with infusion. To date, Grade 4 AEs have included sepsis(1), anemia(1), pleural effusions(1), tachypnea(1), dyspnea(1), and aspiration(1) and Grade 3 AEs have included sepsis(1), leukocytosis(2), DIC(1), tachycardia(1), dyspnea(1), hypotension(1), dusky extremities(1), fatigue(1), ascites(1), peritonitis(1), elevated LFTs(1), portal vein hypertension(1), and acute kidney injury(1). After infusion, CART-meso T cells were transiently detectable by PCR in the peripheral blood in all patients up to Day 21-28 after infusion. CART-meso cells were found to traffic to tumor sites within the peritoneum and liver, as well as to off-tumor on-target sites such as pericardial fluid, but without clinical toxicity of pericarditis. Expansion of CART-meso cells was also observed in the pleural fluid of one patient who had a known malignant pleural effusion. Cytokine profiling of the peripheral blood revealed elevations of IL-6 and VEGF with significant elevations seen in the one patient with malignant pleural effusion. No elevations in TNFα or IFNγ were found. Anti-tumor efficacy is suggested by the clearing of malignant cells in the pleural fluid of one patient on Day 21 and Day 26 after infusion, as well as radiological and clinical evidence of stable to decreased burden of disease in one patient. Patient follow-up for 1-3 months post infusion has revealed no evidence of long-term toxicities to date. These interim results suggest that intravenous infusion of CART-meso T cells without lymphodepletion is feasible and safe. In these five patients with metastatic mesothelin expressing cancers, the infusion was well tolerated with no off-tumor on-target toxicities. Laboratory and clinical findings suggest infused T cells are effective and functional. (emphasis added)
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