Phase Ib study of a plasmid DNA–based immunotherapy encoding the hTERT, PSMA, and WT1 (INO-5401) +/- IL12 (INO-9012) followed by electroporation in cancer patients and healthy individuals with <i>BRCA1/2</i> mutations.

10505 Background: Pathogenic variants in BRCA1/2 increase the risk of breast, ovarian, pancreatic and prostate cancer. Non-surgical risk-reduction strategies are needed. We evaluated an immunological approach for cancer interception via a DNA plasmid vaccine. INO-5401 is a recombinant plasmid-derived DNA based immunotherapy encoding 3 tumor-associated antigens: human telomerase reverse transcriptase (hTERT), prostate specific membrane antigen (PSMA), and Wilms Tumor-1 (WT1). INO-9012 is a DNA plasmid encoding IL-12 deployed as an immune adjuvant. Previous studies have shown that INO-5401 in combination with INO-9012 administered via intramuscular (IM) injection followed by electroporation (EP) with CELLECTRA is both immunogenic and tolerable in cancer patients and may lead to efficacy. Methods: The primary objective of NCT04367675 is to evaluate the safety of INO-5401 +/- INO-9012 followed by EP in individuals with BRCA1/2 . Cohort A included adults with prior localized cancer, no evidence of disease (N = 16); Cohort B, healthy individuals with no prior cancer (goal N = 28). Eligibility: ECOG performance status 0-1, normal ECG, and adequate bone marrow, hepatic, and renal function. Treatment: INO-5401 9 mg IM followed by EP (Arm 1) and INO-5401 9 mg in combination with INO-9012 1 mg IM. followed by EP (Arm 2) on Day 1, and weeks 4, 8, 12. Subjects are assessed at the time of therapy, 2 weeks after each therapy and then every 16 weeks for 2 years. Secondary endpoints (not reported here) include evaluation of immune response. Results: 42 of 44 planned subjects are enrolled and have received &gt;1 vaccine (N = 24 BRCA2 ; N = 15 BRCA1 , N = 3 BRCA1 and BRCA2 ). All doses will be administered by June 2025 and safety data during administration will be complete. In Cohort A, 17 women, 1 man were treated (median age of 52 [range 39-75]). In Cohort B (healthy individuals), 14 women, 12 men were treated (median age of 48 [range 31-69]). 148 doses have been given. One patient received only 1 vaccine due to treatment-related Grade 1 hematoma. Treatment-related AEs were seen in 95% of subjects, largely grade 1 injection site reactions. AEs seen in &gt; 25% are as below. Grade 3 AEs were seen in 6 (15%), including urticaria (N = 1), vasovagal reaction (N = 1), and hypertension (N = 4), none of which were treatment-related. Conclusions: Administration ofa recombinant plasmid-derived DNA based immunotherapy encoding hTERT, PSMA and WT1, +/- IL12, followed by electroporation is feasible and safe in individuals with BRCA1/2 , including healthy individuals with no prior cancer. The most common AEs are injection site reactions, all of which were Grade 1/2. Clinical trial information: NCT04367675 . CTCAE Term Grade 1 Grade 2 Frequency Pain N=26 N=3 72.5% (N=29) Bruising N=26 N=0 65.0% (N=26) Swelling N=19 N=0 47.5% (N=19) Redness N=14 N=0 35.0% (N=14) Injection Site Reaction N=11 N=2 32.5% (N=13)