Background: Tisa-cel showed durable responses and manageable safety in pts with r/r DLBCL in the phase 2 JULIET trial. High baseline programmed cell death 1 (PD-1) expression associated with higher probability of no response (Schuster et al. NEJM 2019). Here we report an updated analysis of PORTIA, a phase 1b, multicenter, open-label study of tisa-cel plus pembro in pts with r/r DLBCL. Methods: Eligible pts (≥18 y) had r/r DLBCL after ≥2 lines of therapy and relapsed after or were not candidates for autologous stem cell transplant (autoSCT). Patients received a single tisa-cel infusion on Day 1 and were enrolled in 1 of 3 cohorts that initiated pembro (200 mg q 21 days, for up to 6 doses) on either Days +15, +8, or –1. Primary endpoints were incidence of dose-limiting toxicities (DLTs) and overall response rate (ORR; complete response [CR] and partial response [PR]). Secondary endpoints included duration of response, progression-free survival, overall survival, safety, and cellular kinetics. Results: As of November 9, 2020, 15 pts were enrolled and 12 received tisa-cel (n = 4 pts for each Days +15, +8, and –1 cohorts; median follow-up, 4 mo). At study entry, the median age among treated pts was 62 y (range, 35-79), 100% had an International Prognostic Index score ≥2, 67% had ≥3 prior lines of therapy, 58% had stage IV disease, 58% had lactate dehydrogenase > ULN, and 42% had prior autoSCT. All 12 pts had ≥1 AE. Grade ≥3 AEs suspected to be related to tisa-cel and/or pembro were neutropenia (n = 4); neutrophil count decreased (n = 3); febrile neutropenia, lymphocyte count decreased, malnutrition (each n = 2); anemia, leukopenia, diarrhea, white blood count decreased, liver function tests increased, thrombocytopenia, hepatitis, and cytokine release syndrome (CRS; each n = 1). No neurotoxicity or DLTs were observed. Among the Day +15, +8, and –1 cohorts (each n = 4), the ORR was 50% (2/4; CR n = 0, PR n = 2), 25% (1/4; CR n = 1, PR n = 0), and 25% (1/4; CR n = 1, PR n = 0; longer follow-up is needed for n = 2 pts), respectively. Tisa-cel exposure and peak expansion were consistent with JULIET, with a trend toward delayed expansion in the Day –1 cohort (n = 4). There was no sign of secondary expansion following pembro administration regardless of the number of doses. Compared with JULIET, lower CRS severity and frequency and lower cytokine profiles were observed for all 3 cohorts. Conclusions: The combination of tisa-cel plus pembro was feasible and showed manageable safety. The lack of improved efficacy in PORTIA with the addition of pembro compared with tisa-cel alone may be related to more pts with ≥3 prior lines of therapy (67% vs 51%, respectively), and/or pts with more advanced disease in PORTIA. Additional studies with larger patient cohorts are needed to determine the value of adding PD-1 inhibitors to CAR-T cell therapy in pts with r/r DLBCL. Clinical trial information: NCT03630159