In this study we examined the safety and feasibility and antitumor efficacy of Transgenic adoptive cell therapy (ACT) with Dendritic Cell (DC) vaccination, with and without CTLA-4 blockade with ipilimumab. Results reveal the treatment is feasible and results in transient antitumor activity, with no apparent clinical benefit of the addition of ipilimumab.
20 patients with unresectable or recurrent pancreatic cancer histologically confirmed as invasive ductal carcinoma. Eleven of the 20 patients showed liver metastasis and 5 showed peritoneal dissemination. One patient showed lung metastasis, but no liver metastasis or peritoneal dissemination. Fifteen of the 20 patients were stage IV and 5 were stage III according to the TNM staging of the UICC, and all showed histologically confirmed invasive ductal carcinoma of the pancreas. Sixteen of the twenty patients did not receive chemotherapy. Four patients had received gemcitabine prior to the present AIT.
Patients were then admitted and received lymphodepleting chemotherapy consisting of cyclophosphamide 60 mg/kg/day x2 days intravenously on days -5 and -4, and fludarabine 25 mg/m2/day x4 days intravenously from day -4 to -1.
Patients received their first dose of 1 mg/kg ipilimumab, intradermal administration of NY-ESO1 peptide–pulsed DCs and began low-dose IL2 therapy (500,000 IU/m2 s.c.) the following morning (day +1) twice daily for up to 28 doses (patients ESO-1, ESO-2, ESO-3, ESO-4, INY-1, INY-2) or 14 doses (patients ESO-5, ESO-6, INY-3, and INY-4), as tolerated.
Patients continued to receive two more doses of DC vaccines at 2-week intervals and 1 mg/kg ipilimumab every three weeks for four total doses (if on the INY protocol).Six patients were enrolled in the ESO cohort, and four were enrolled in the INY cohort.
Safety and feasibility
There were no serious toxicities in all 10 patients in both protocols beyond known toxicities that were attributed to the conditioning chemotherapy, systemic IL2 therapy, and ipilimumab therapy, and these serious toxicities were generally reversible.
At the formal restaging PET/CT scans on day +90, 2 of the patients treated per ESO had evidence of a partial response by RECIST1.1. One patient treated per ESO had a partial response (PR) that eventually progressed to a complete response (CR) without additional therapy and has had an ongoing CR for over four years.
Clinical responseIn ESO cohort, 2 patients achieved partial response (both synovial sarcoma) with OS of 43 and 51 months (progressed to complete response). 2 patients had progressed disease (osteosarcoma and synovial sarcoma) with OS of 19 months and 25 months respectively.In INY cohort, all 4 patients had progressed disease with OS of 2, 3, 6 and 29 months.
In conclusion, the manufacture and administration of transgenic NY-ESO-1 TCR T cells with NY- ESO-1 peptide-pulsed DC vaccine with or without ipilimumab is generally safe, feasible, and results in frequent initial antitumor activity. Addition of ipilimumab, while safe and feasible, had no apparent effect on transgenic cell persistence, transgenic cell phenotype, or overall clinical response.