A phase I trial targeting advanced or metastatic pancreatic cancer using a combination of standard chemotherapy and adoptively transferred nonengineered, multiantigen specific T cells in the first-line setting (TACTOPS).

Abstract

4622 Background: Immunotherapy is emerging as a potent therapy for a range of hematologic malignancies and solid tumors. To target pancreatic carcinoma we have developed an autologous, non-engineered T cell therapy using T cell lines that simultaneously target the tumor-associated antigens (TAAs) PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin. These multiTAA-specific T-cell lines could be consistently prepared by culturing PBMCs in the presence of a Th1-polarizing/pro-proliferative cytokine cocktail, and adding autologous pepmix-loaded DCs as APCs. Methods: Patients with locally advanced or metastatic pancreatic adenocarcinoma who achieved cancer control with three months of standard chemotherapy were eligible to receive up to 6 infusions of multiTAA T-cells (fixed dose - 1x107 cells/m2). While also continuing the same chemotherapy, T-cells were given at monthly intervals from month four, onwards. The primary study endpoints were safety and feasibility of completing all 6 planned infusions, with secondary and tertiary endpoints including anti-tumor effects, patient survival, in vivo expansion and T cell persistence of the infused cells as well as recruitment of the endogenous immune system. Results: Between June 2018 and December 2019, we treated 13 patients with multiTAA T-cells. For 12/13 patients, we generated sufficient cells for all 6 planned doses; 2 doses were available for the remaining patient. Of the 13 patients, 8 maintained cancer control for a longer than expected duration, compared to historical controls. With administration of T-cells, 3 of these 8 patients had partial responses and 1 patient had a radiographic complete response (per RECIST). These responses were seen in patients with metastatic cancer. Notably, no patient had infusion-related systemic- or neuro-toxicity. Thus, infusion of autologous multiTAA-targeted T cells directed to PRAME, SSX2, MAGEA4, NY-ESO-1 and Survivin has been safe and provided durable clinical benefit to patients with pancreatic adenocarcinoma. Conclusions: Autologous, TAA cytotoxic T-cells can reliably be generated and safely administered to patients in conjunction with standard of care chemotherapy. In some patients, addition of T-cells may extend duration of first line therapy cancer control and induce additional tumor responses, and activation of the endogenous immune system has been documented in all patients. Exploration in a higher phase study is warranted. Clinical trial information: NCT03192462 .

Autologous engineered T cell receptor therapy in advanced cancer

“…The combination of autologous, non-engineered, multi-target T cells with chemotherapy has been associated with extended tumor control in multiple myeloma, 29 melanoma 30 and pancreatic cancer. 31 In our trial, the engraftment and persistence of T cells exhibited a favorable profile compared to previously reported data with similar ACT approaches. 32 Importantly, T-cell persistence is necessary for achieving prolonged PFS.…”

Immunologic Strategies in Pancreatic Cancer: Making Cold Tumors Hot

“…Of these eight metastatic patients, three had PR and one had CR. 105 Although adoptive cell transfer is a new and promising field of immunotherapy, it possesses many limitations. Antigen selection poses a significant hurdle for CAR-T as most studies to date target tumor-associated antigens, rather than TSAs.…”

Emerging Challenges to Cellular Therapy of Cancer

“…Five days after T-cell infusions, both patients died of cardiogenic shock, because the affinity enhancement of the TCR permitted cross-reactivity toward a similar HLA-A01–restricted peptide derived from the normal cardiomyocyte protein Titin 33 . To overcome these unwanted on-target, off-tumor effects, contemporary trials have looked at reducing the affinity for target epitopes or reducing the total dose of administered T cells 34–38 . For example, we have safely and effectively treated cancer patients with nonengineered T cells that are not affinity enhanced but possess native TCRs specific for cancer-testis antigens (including the MAGE group of antigens) (Table 2).…”

“…33 To overcome these unwanted on-target, off-tumor effects, contemporary trials have looked at reducing the affinity for target epitopes or reducing the total dose of administered T cells. [34][35][36][37][38] For example, we have safely and effectively treated cancer patients with nonengineered T cells that are not affinity enhanced but possess native TCRs specific for cancer-testis antigens (including the MAGE group of antigens) (Table 2).…”