Nivolumab/ipilimumab primed immunotransplant in post-CAR-T and post-ASCT DLBCL.

2593 Background: Patients with refractory diffuse large b cell lymphoma (DLBCL) have poor outcomes with < 30% surviving for 12 months and especially poor outcomes for those who progress after chimeric antigen receptor T cells (CAR-T) or autologous stem cell transplant (ASCT). These therapies utilize lymphodepleting chemotherapy which induces homeostatic T cell proliferation. We have demonstrated these expanding T cells express high levels of PD1 and CTLA4. In pre-clinical models, addition of dual checkpoint blockade (DCB) with anti-PD1/anti-CTLA-4 to adoptive T cell transfer after lymphodepletion achieved a synergistic anti-tumor effect. Based on these studies, we developed a phase Ib/II study of Nivolumab/Ipilimumab primed “immunotransplant” for relapsed/refractory (R/R) DLBCL (NCT03305445). Methods: Phase Ib of the trial enrolled 6 patients with progressive disease following at least one line of standard therapy. Patients received two cycles of DCB with ipilimumab (1mg/kg) and nivolumab (3mg/kg) given at three-week intervals followed by immunotransplant (i.e. peripheral blood T cell harvest, lymphodepletion with fludarabine/cyclophosphamide, T cell reinfusion), followed by two further cycles of DCB and nivolumab maintenance. Results: Five patients received at least two cycles of DCB and the autologous T cell transfer, while one patient had progressive disease during initial DCB and required salvage chemotherapy. Treatment emergent AE (TEAE) occurred in 100% of patients. As expected with lymphodepleting chemotherapy, the most common TEAE were neutropenia (66.7% grade 1, 66.7% grade ≥ 3), fatigue (83.3%, 16.7%), fever (66.7%, 0%), and dyspnea (66.7%, 0.0%). One patient (16.7%) died during the intervention period (grade 5 TEAE), though relation to study drug is unclear. Three patients (50.0%) experienced clinical benefit with immunotransplant. One patient (a 58yo M with progression after seven lines of therapy including ASCT and CAR-T) is experiencing partial metabolic response after 4 months on protocol. One 77yo F with multiple prior lines of therapy including ASCT has experienced an extended complete metabolic response, currently 31 months post immunotransplant. A third (a 50yo F) experienced mixed radiographic response, and has not received subsequent therapy 30 months following immunotransplant. Conclusions: Nivolumab/Ipilimumab primed immunotransplant is well tolerated in patients with R/R DLBCL for whom there are few treatment options. Preliminary results demonstrate remissions in heavily pre-treated patients, including prior ASCT and CAR-T. Pre-clinical models in melanoma, non-small cell lung cancer, and T cell lymphoma all demonstrate synergy when DCB is administered with lymphodepletion and autologous T cell transfer. These data support further investigation of DCB-primed immunotransplant. Clinical trial information: NCT03305445.