Wiseman, Charles L.

e13124 Background: Bria-IMT, an allogeneic whole-cell cancer vaccine (SV-BR-1-GM), was administered w/ an anti PD1 checkpoint inhibitor (CPI) to evaluate its safety and efficacy in advanced/metastatic breast cancer (MBC). SV-BR-1-GM breast cancer cells were engineered to directly stimulate anti-tumor immunity through expression of tumor associated antigens and secretion of GM-CSF to enhance endogenous dendritic cell activation. Addition of a CPI potentiates SV-BR-1-GM action by overcoming the immune suppressive tumor microenvironment and may have a differential impact vs monotherapy SV-BR-1-GM. Methods: In this exploratory analysis of the Phase 1 + randomized Phase 2, HLA matching status was assessed to explore potential correlations w/ clinical outcomes. Pts were stratified by overall HLA match by Class I or II (0 vs ≥1 matches), formulation and MBC subtype to assess objective response rate (ORR), clinical benefit rate (CBR), progression free survival (PFS), and overall survival (OS). Partial HLA matching (≥1 Class I and ≥1 Class II allele) was also analyzed. Results: In the total pt population, the ORR was 10%, CBR 56%, PFS 3.2 months and OS 9.9 months. In those pts treated w/ the phase 3 formulation, ORR was 15%, CBR 63%, PFS 3.6 months and OS 13.4 months. Using available HLA data (n = 52), 25% had 0, 34.6% 1, 32.6% 2, and 8% ≥3 matches. While OS and PFS were greater (Undefined vs 8.5 mos ; p = .02) in pts without an HLA match compared w/ those w/ ≥1 match (see Table), ORR and CBR were similar. This was also the case for pts who had 0 HLA Class I matches vs those w/ ≥1 Class I match (15.6 vs 7.2 mos; p = .002). ORR, CBR, PFS and OS were generally similar for pts who had 0 Class II HLA matches vs those w/ ≥1 match. Pts who matched at least at 1 Class I and 1 Class II allele had a higher ORR and CBR than those who matched at a single Class I or a single Class II allele although PFS and OS were similar between the groups. Similar observations were seen for pts treated w/ the phase 3 formulation. Conclusions: Matching at Class I seemed to decrease PFS & OS, but did not have a similar effect on ORR and CBR. Both matched and non matched pts demonstrated favorable OS and response rates. These findings support further investigation into specific mechanisms and the clinical significance of HLA matching in immunotherapy response. A randomized phase 3 trial is ongoing comparing Bria-IMT vs treatment of physician's choice (NCT06072612). Clinical trial information: NCT03328026 . n (Evaluable) % of Cohort Best ORR Best CBR PFS OS Full Cohort 52 (41) 10% 56% 3.2 9.9 No Match (Overall) 13 (10) 25% 20% 60% 4.2 Undefined Any Match (Overall) 39 (31) 75% 6% 55% 3 8.5 MHC Class I No Match / Any Match 27 (20) / 25 (21) 52% / 48% 10% /10% 55% /57% 3.5 / 2.7 15.6 / 7.23 MHC Class II Any Match 27 (19) 52% 11% 63% 3.2 11.4 MHC Class I&II Match 13 (9) 25% 22% 77% 2.8 8.6 Phase 3 Formulation (N=35) 35 (27) 15% 63% 3.57 13.43 No Match (Phase 3 Formulation) 11 (9) 31% 22% 67% 5.6 Undefined MHC Class I&II Match (Phase 3 Formulation) 11 (7) 31% 29% 71% 2.7 7.23

1096 Background: Bria-IMT is a combination immunotherapy consisting of allogeneic whole cell cancer vaccine (SV-BR-1-GM) administered w/ immune checkpoint inhibitor (CPI). SV-BR-1-GM breast cancer cells are engineered to directly stimulate anti tumor immunity via expression of tumor associated antigens and secretion of GM-CSF to enhance dendritic cell activation. Addition of CPI potentiates SV-BR-1-GM to overcome the immune suppressive tumor microenvironment. Methods: This Ph I/randomized Ph II study evaluated the Bria-IMT regimen in pts w/ metastatic breast cancer; CTX (300 mg/m²) on day -2/-3, SV-BR-1-GM and CPI on Day 0, w/ low dose peg interferon α at inoculation sites on day 2 (±1) . Phase II pts were randomized 1:1 to receive CPI at cycle 1 or cycle 2. Two SV-BR-1-GM formulations (w/ vs w/o IFNγ incubation) were evaluated. Biomarkers included cancer-associated macrophage-like cells, circulating tumor cells, PD-L1 scores, and delayed-type hypersensitivity skin tests. Results: 54 pts (22 Ph I, 32 Ph II) enrolled; 11 received pembrolizumab, 44 retifanlimab (1 crossover). 33 (61%) pts were ER+/PR+/HER2-, 18 (33%) TNBC, 3 (6%) HER2+. Median OS, PFS, ORR, and CBR were evaluated against two pivotal Ph 3 trials, ASCENT 1 (SG in TNBC) and TROPiCS-02 2 (SG in HR+/HER2- MBC) (see Table 1). In randomized pts, C1 vs C2 CPI had PFS (3.7 vs 3.2 mos, P=0.09) and OS (11.4 vs 7.4 mos, P=0.19). Pts receiving Ph 3 formulation (w/o IFNγ; N=37) had greater PFS (3.6 vs 2.6 mos, P=0.01) and OS (13.4 vs 6.9 mos, P=0.01). Bria-IMT was well tolerated w/ no Tx related D/Cs. Conclusions: The Bria-IMT Ph 3 formulation cohort OS was comparable to ASCENT and TROPiCS-02 (13.43 vs 11.8, 14.4 mos), exceeding TPC arms (6.9, 11.2 mos). CBR (61%) compared favorably to ASCENT (40%) and TROPiCS-02 (34%); ORR (14%) matched or exceeded TPC arms (4%, 14%). These outcomes were observed in a more heavily pretreated population, demonstrating Bria-IMT’s clinical activity. Randomized Ph 2 results suggest efficacy and safety in heavily pretreated MBC, w/ no significant OS difference between C1 and C2 CPI initiation and 22% of pts still in active survival follow up. Superior outcomes w/ the Ph 3 formulation support its continued evaluation. A randomized Ph 3 trial is ongoing, comparing Bria-IMT vs treatment of physician’s choice (NCT06072612). Clinical trial information: NCT03328026 . Trial (Cohort) Age (Median, Range) Prior Therapies (Median) OS (Median, mos) PFS (Median, mos) ORR (%) CBR (%) Bria-IMT (Overall Cohort) 61 (38-81) 6 (2-13) 9.9 (1.8-30.3) 3.6 10% 55% Bria-IMT (Ph 3 Formulation) 62 (44-80) 6 (2-13) 13.43 (1.8-30.3) 3.6 (1.8-16.5) 14% 61% ASCENT (SG) 54 (27-82) 4 (2-17) 11.8 4.8 31% 40% ASCENT (TPC) 53 (27-81) 4 (2-14) 6.9 1.7 4% 8% TROPiCS-02 (SG) 57 (49-65) 3 14.4 5.5 21% 34% TROPiCS-02 (TPC) 55 (48-63) 3 11.2 4 14% 22% References: Bardia A et al. J Clin Oncol. 2024 May 20;42(15):1738-1744Rugo, Hope S et al. The Lancet, Volume 402, Issue 10411, 1423 – 1433.

Abstract Background: Bria-IMT™ is a combination immunotherapy consisting of allogeneic whole-cell cancer vaccine (SV-BR-1-GM) administered w/ immune checkpoint inhibitor (CPI). SV-BR-1-GM breast cancer cells have been engineered to directly stimulate anti-tumor immunity through expression of tumor-associated antigens and secretion of GM-CSF to enhance dendritic cell activation. Addition of CPI potentiates SV-BR-1-GM to overcome the immune-suppressive tumor microenvironment. Methods: This Phase I and randomized phase II combination study evaluated the Bria-IMT™ regimen: preconditioning w/ CTX (300 mg/m2) on day -2 or -3, SV-BR-1-GM inoculation and CPI administration on Day 0, and low-dose peg- interferon α at inoculation sites 2 (±1) day post-SV-BR-1-GM. Phase II pts were randomized 1:1 to receive CPI at cycle 1 (immediate) or cycle 2 (delayed). Two SV-BR-1-GM formulations (w/ and w/o IFNγ incubation) were evaluated. Biomarkers included cancer-associated macrophage-like cells (CAMLs), circulating tumor cells (CTCs), PD-L1 scores, and delayed-type hypersensitivity (DTH) skin tests. Results: 54 pts (22 in Phase I, 32 in Phase II) enrolled. 11 pts received pembrolizumab, 44 retifanlimab, w/ 1 pt transitioning from pembrolizumab to retifanlimab. Median age 61(38-81) years; median 6(2-13) prior regimens. 33(61%) pts were ER+/PR+/HER2-, 18(33%) TNBC, and 3(6%) HER2+. Bria-IMT regimen was well tolerated, w/ no attributable Tx D/C. 67% of adverse events grade 1-2; 13% ≥ grade 3 including pulmonary embolism, increased lipase, and dehydration. Median overall survival (OS) was 9.9 (1.8 - 30.3) mos w/ 13% of pts in active survival follow-up. Median progression free survival (PFS) was 3.2 (1.1-16.5) mos w/ 1 pt still in treatment (16.5 mos). Pts treated w/ ph 3 formulation (w/o IFNγ; N = 37) had significantly improved PFS (3.6 vs. 2.6 mos, P=0.01) and OS (13.4 vs. 6.9 mos, P=0.01); in evaluable pts, objective response rate was 14% and clinical benefit rate 61%. Randomized pts receiving ph 3 formulation had not reached median OS. In randomized pts, C1 vs C2 CPI initiation showed greater PFS (3.7 vs. 3.2 mos, P=0.09) and OS (11.4 vs. 7.4 mos, P=0.19). OS in pts w/ no HLA match was undefined vs 8.6 mos in pts w/ any match (P = 0.04). DTH (+) vs (-) correlated w/ greater OS (11.9 vs. 4.7 mos, P= <0.0001) and PFS (3.5 vs. 2.4 mos, P=0.001). Conclusion: Randomized phase 2 Bria-IMT demonstrated efficacy and safety in heavily pretreated MBC. Post-progression survival exceeding median OS in pts still undergoing survival follow-up suggests long-term benefit extending beyond treatment period. C1 vs C2 CPI initiation showed no statistical or clinically significant difference in OS. Superior outcomes w/ phase 3 formulation support its use in future trials. These results confirm earlier reports of the trial and an even greater benefit. A randomized phase 3 trial is ongoing comparing Bria-IMT vs treatment of physician's choice (NCT06072612). Trial Information: NCT03328026 Citation Format: Saranya Chumsri, Chaitali Nangia, Minal Barve, Kendrith Rowland, Ralph Boccia, John Knecht, Blaise Bayer, Marcela Salgado, Tamar Aghajanian, William V. Williams, Charles Wiseman, Giuseppe Del Priore, Carmen Calfa. Survival outcomes in a randomized phase 2 ofBria-IMT: An allogeneic whole cell cancer vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT100.

e13119 Background: Breast cancer metastasis to the central nervous system (CNS) and intracranial area often leads to severe morbidity and mortality. While systemic treatments manage systemic tumors, their impact on CNS/intracranial metastases is limited. Cell based therapies like SV-BR-1-GM may overcome this limitation. SV-BR-1-GM is a GM-CSF secreting, antigen-presenting immortalized breast cancer cell line. We report its efficacy on CNS tumor regression. Methods: Post-hoc analysis of a subset of all advanced MBC patients with CNS/intracranial metastases from previous phase 1, 2, and an ongoing randomized phase 2, trials (n=7 subjects) of SV-BR-1-GM. Bria-IMT monotherapy (intradermal SV-BR-1-GM + cyclophosphamide 300 mg/m2, +interferon-alpha) was administered q3wks to 2 subjects; an immune checkpoint inhibitor (ICI) was administered with each cycle in the combination setting (n=5). Results: There were 7 patients with intracranial metastases at baseline of whom 5 had intracranial tumor responses. Of the 5 responders, median pt age = 66 (range 58-70), median prior lines = 5.5 (3-13), and median time from initial diagnosis = 7.5 years (3-10). 4/5 pts had ≥1 HLA class match with SV-BR-1-GM. 3 were HR + and 1 HER2 +. Pt A002 (ER+/PR+, HER2-) received 6/6 planned cycles, achieving an 83% reduction in breast lesions; after 3 months off therapy, imaging revealed multiple brain metastases and recurrence of right breast lesions. Following 3 additional cycles there was marked regression in both brain and breast lesions. Pt 02-003 (ER-/PR-, HER2 1+ (IHC)) received 5 cycles of SV-BR-1-GM and observed a 60% reduction (5mm -> 2mm) in a left parietal periventricular lesion, and complete resolution (CR) of a left parietal lobe. Pt 06-005 (ER+/PR-, HER2 1+) demonstrated a 56% (9mm -> 4mm) reduction in the thickness of a dural lesion overlying the left anterior temporal lobe after 6 cycles of SV-BR-1-GM + ICI. After 2 additional cycles of SV-BR-1-GM + ICI and 1 cycle of SV-BR-1-GM (ICI skipped on final cycle due to grade 2 AE), patient achieved CR of a left orbital mass observed at baseline (24mm -> 0m). Pt06-007’s (ER-/PR-, HER2 1+) CNS lesions showed a median reduction of 49% compared to baseline after 3 cycles. Pt 11-018 (ER+/PR-, HER2 +) showed standard progression (SD) at initial restaging; 14% increase in sum of diameters of intracranial metastasis. Subsequent imaging, after 3 cycles, showed significant orbital tumor reduction along with reported improvement in eye pain. Conclusions: This post-hoc analysis demonstrated promising efficacy of the Bria-IMT regimen either alone or in combination with ICIs in CNS/intracranial metastasis. The CNS/intracranial regression seen across all breast cancer subtypes among heavily pretreated patients highlights the potential of SV-BR-1-GM in managing CNS metastasis. Ongoing trials will further evaluate the efficacy of the Bria-IMT regimen in patients with CNS/intracranial metastasis. Clinical trial information: NCT03328026 .

1087 Background: Antibody-drug conjugate (ADC) sequencing raises concerns of cross-resistance due to their shared targets and cytotoxic payloads. Consequently, treatments after ADCs in heavily pretreated MBC is uncertain. SV-BR-1-GM, a GM-CSF secreting, antigen-presenting immortalized breast cancer cell line, has emerged as a post ADC solution (1) based on a different MOA. We now report the results of SV-BR-1-GM in ADC treated patients. Methods: Post-hoc analysis of an ongoing randomized Phase 2 censored to the data-cut date prior to data lock. Bria-IMT (~20x106 SV-BR-1-GM cells, intradermally 48-72 hours after ctx (300 mg/m2), followed by interferon-alpha 2 days later) administered q3wks with a checkpoint inhibitor (CPI). Adverse events were classified according to their severity and relationship to treatment regimen. Results: Among 54 advanced MBC patients randomized, 23 who failed prior ADC therapy were identified. All were heavily pretreated (median 6 prior lines, range 3 – 13). Median age 62 (41-83). 14 pts had HR+/HER2-, 5 TNBC, and 2 HR+/HER2+ MBC. The remaining were HR-/HER2+ or HR-/HER2 low. 8 pts received > 1 ADC. Prior ADCs included: 4 ado-trastuzumab emtansine, 14 trastuzumab deruxtecan, 13 sacituzumab govitecan. 7 pts had also received ≥ 1 prior CPI line. To date, pts received a median 3 cycles of Bria-IMT™ + CPI (2-8). Kaplan-Meier analysis revealed a median OS of 42 weeks with survival of 69% at 6 months. The subset experienced a median PFS of 74 days with 40% of pts demonstrating a Bria-IMT PFS (PFS2) similar to or > their prior line PFS (PFS1). 39% of pts experienced a PFS2 ≥ their most recent line of ADC PFS. The disease control rate was 40% among evaluable pts. 43% of pts had a reduction in cancer-associated macrophage-like cell (CAML) levels; median reduction was 36% (22-98%) after 1 cycle. There were no toxicity-related treatment discontinuations. 43% (10/23) reported grade 3 or 4 AEs, independent of study drug causality. AEs included injection site reaction (39%), fatigue (26%), and nausea/vomiting (43%), mostly mild to moderate. One case of elevated lipase was the most clinically significant grade 4 AE. No interstitial lung disease (ILD) was reported. Conclusions: This subset analysis of the Bria-IMT regimen in ADC refractory MBC patients suggests a potential clinical benefit and treatment option for this patient population. The absence of serious AEs, notably interstitial lung disease (ILD), and no toxicity-related treatment discontinuations, underscores the regimen's favorable safety profile. Future studies are warranted to confirm these results and explore the potential of Bria-IMT™ in broad clinical settings of heavily pretreated contemporary MBC patients. 1. Kamaraju 2024 AACR. Clinical trial information: NCT03328026 .

1022 Background: The Bria-IMT regimen is a combination immunotherapy using an allogeneic whole cell cancer vaccine combined with checkpoint inhibitors (CPIs). Intradermally administered irradiated SV-BR-1-GM breast cancer cells secrete GM-CSF and present tumor associated antigens (TAAs) on HLA-I and –II molecules to directly stimulate anti-tumor immunity. Anti-PD1 CPI further stimulates T-cells and synergizes with SV-BR-1-GM. Here we report the results of the phase 1/2 trial (NCT03328026) of Bria-IMT in metastatic/advanced breast cancer evaluating sequencing of SV-BR-1-GM inoculation and CPI. Methods: Analysis of the phase 1 with expansion phase 2 cohort randomized by sequence using SV-BR-1-GM, checkpoint inhibitor (pembrolizumab or retifanlimab), low dose cyclophosphamide (Day –2) and post-dose local pegylated interferon α, with cycles every 3 weeks. In the 1:1 randomized cohort, CPI is either dosed at C1 prior to SV-BR-1-GM (original sequence) or delayed to C2 post-SV-BR-1-GM (alternative sequence). Cancer-associated macrophage-like cells (CAMLs) and circulating tumor cells (CTCs) were monitored as biomarkers. Results: A total of 54 patients were dosed: 11 with pembrolizumab, 44 with retifanlimab (1 patient received pembrolizumab and later retifanlimab). Median age=61 (38-81); Median prior regimen=6 (2-13); 72% ER+/PR+/HER2-; 6% HER2+ and 22% triple negative. Bria-IMT regimen was well tolerated with only 9% drop-out rate due to AE. AEs related to IPs were seen in 74% of patients; the majority (91%) being grade 1-2, and few (1.7%) grade 4 cases including pulmonary embolism, dehydration and increased lipase. Among 30 patients with post-dose CAML/CTC data and evaluable outcome, CAML count <5 associates with disease control (p=0.06, Chi square test). Patients who developed DTH to SV-BR-1-GM had significantly better PFS and higher OS. Patients treated with phase III formulation had an increase in PFS. Quality of life improvement correlates with disease outcome and survival. Among the patients treated with the phase III formulation of SV-BR-1-GM (n=23 with evaluable outcomes), objective response rate (ORR) is 13% and disease control rate (DCR) is 61%, with median PFS and OS are 4.1 and 13.3 months, respectively. In the randomized portion, the original sequence cohort had higher DCR (43% vs 36%) and OS (P=0.08, HR 0.30, 95%CI 0.08-1.17) compared to the alternative sequence cohort. Conclusions: BRIA-IMT has shown a favorable safety profile while providing benefits to heavily treated aMBC patients. Superior outcomes and survival were seen in patients treated with the phase III formulation and regimen now being used in the ongoing Ph3 trial, confirming the improvement in efficacy of the novel regimen. The results from this randomized phase 2 study informed the study design of the ongoing Ph3 trial comparing BRIA-IMT to standard of care physician choice treatments (NCT06072612). Clinical trial information: NCT03328026 .

Abstract Introduction Despite progress in MBC, too many continue to succumb due to treatment resistance or intolerance. SV-BR-1-GM is an allogenic human breast cancer cell line with antigen presenting cell activity designed to overcome the immune-suppressive tumor microenvironment while being acceptable to extensively pretreated contemporary MBC patients. We report interim exploratory analysis of the ongoing RCT of the Bria-IMT regimens. Methods An interim exploratory analysis using preliminary partially available evaluable data of the ongoing prospective, randomized phase 2 (NCT03328026; 2018-present) of Bria-IMT (irradiated SV-BR-1-GM) with a PD-1check point inhibitor (CPI) every 3 weeks (25 patients dosed to date). Both regimens include cyclophosphamide 300 mg/m2 48-72 hours prior to intradermal Bria-IMT (~20 x 106 cells) followed by interferon-alpha at the inoculation sites 2 days later. The control arm used the original sequence with simultaneous start of Bria-IMT and CPI in cycle 1. The experimental arm started CPI in cycle 2 after the 2nd inoculation. Candida skin test was performed before cycle 1 to determine anergy status while delayed-type hypersensitivity skin test (DTH), defined as &gt;5mm erythema & induration, was done at every cycle by intradermal injection of a small test dose of Bria-IMT prior to full dose inoculation. Results Median age: 58 (range 37-81); median prior therapies: 8 lines (range 4-18); 89% were grade 2/3 (n=18); 68% hormone receptor positive; 61% HER2 negative, 33% HER2 low, and 6% HER2 high; 33% triple negative. Overall, 53% of subjects had a clinical benefit as best response by BICR, PI or target lesion measurement. The two treatment arms were similar with a trend showing longer median durations on therapy (mDOT) of 3.7 mo in the experimental delayed CPI arm compared with mDOT = 2.9 for original sequence control arm. 47% of patients were anergic to candida. Among all anergic subjects, the mDOT was 3.5 compared to 2.5 mo for non-anergic patients. However, among anergic subjects, the alternative treatment arm had a lower risk of treatment discontinuation (improved HR) with mDOT of 3.7 compared to the 3.3 mo mDOT of the original treatment. 50% of anergic subjects eventually developed DTH to SV-BR-1-GM. mDOT was 4.0 mo for DTH+ pts vs 3.0 mo for those who did not mount DTH. Median OS was not yet reached; mean OS was higher in non-anergic vs anergic pts. Among those who developed an inoculation site reaction to Bria-IMT, OS was greater than for those who did not. Time on the Bria-IMT regimen exceeded the time on penultimate treatment in 22% of subjects while 33% of subjects with prior CPI use exceeded last therapy. AEs were mild with 28% of subjects (n=7) having &gt; grade 3 events. The most common grade 3+ AE was lipase increase (n=3). One subject with encouraging changes in peripheral blood tumor markers and CTCs completed a PET study using Zr-89 crefmirlimab berdoxam, a zirconium-89 labelled truncated antibody specific to human CD8α (CD8 Immuno-PET) and demonstrated increased uptake in some metastatic lesions and draining lymph nodes. Updated results will be provided at the meeting. Conclusion Sequencing of CPI with Bria-IMT is associated with differential clinical outcome trends but not statistically significant in this interim preliminary exploratory analysis regardless of prior CPI use. Bria-IMT is immunogenic with clinical benefit demonstrated for both treatment schedules among patients with inducible DTH reactions. Patients who develop an immune response to Bria-IMT had an increase in OS compared to those who did not. The nodal localization of CD8+ cells on PET may indicate a systemic activation of CD8 positive lymphoid cells. It also provides support that the Bria-IMT + CPI combination immune-based therapy can result in an increase of CD8+ tumor infiltrating lymphocytes in breast cancer metastatic sites. These preliminary results will be evaluated in the ongoing randomized phase 3 pivotal registrational trial. Citation Format: Carmen Calfa, Chaitali Nangia, Minal Barve, John Knecht, Jarrod Holmes, Kendrith Roland, Ralph Boccia, Frances Valdes-Albini, Zach Gostout, Mingjin Chang, William Williams, Charles Wiseman, Bonnie Guerin, Shaker Dakhil, Giuseppe Del Priore, Saranya Chumsri. Randomized Phase 2 of Bria-IMT, an Allogenic Human Cell Line with Antigen Presenting Activity, in Heavily Pretreated Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-12.

Abstract Background: Antibody-drug conjugate (ADC) sequencing raises concerns of cross-resistance due to their shared cytotoxic payloads. Consequently, there is a pressing need for treatments after ADCs, especially in heavily pretreated patients. Immunization with irradiated SV-BR-1-GM, a GM-CSF secreting, antigen-presenting immortalized breast cancer cell line, has emerged as a potential post ADC solution based on a different mechanism of action. This retrospective analysis aims to assess the overall efficacy and safety of SV-BR-1-GM in a subset of ADC treated patients. Methods: Post-hoc subset analysis of the ongoing randomized Phase 2 study identified 23 advanced MBC patients who failed prior ADC therapy. Bria-IMT™ (irradiated SV-BR-1-GM ~20x106 cells, intradermally 48-72 hours after cyclophosphamide (300 mg/m2), followed by interferon-alpha at the inoculation sites 2 days later) was administered q3wks with a CPI. Endpoints included PFS, OS and disease control rate (the proportion of patients with stable disease, partial or complete responses) using the KM method censored to the data-cut date prior to data lock. Adverse events were classified according to their severity and relationship to treatment regimen. Results: All pts were heavily pretreated (median 6 prior lines, range 3 - 13). Median age was 62 (41-83). 14 pts had HR+/HER2-, 5 TNBC, and 2 HR+/HER2+ MBC. The remaining pts were HR-/HER2low or HR-/HER2+. Prior ADCs included: 4 ado-trastuzumab emtansine, 14 trastuzumab deruxtecan, 13 sacituzumab govitecan; 8 pts received &gt; 1 ADC. 7 pts had also received ≥ 1 prior CPI line. To date, pts received a median 3 cycles of Bria-IMT™ + CPI (2-7). Kaplan-Meier analysis revealed a median OS of 42 weeks with survival of 69% at 6 months. The subset experienced a median PFS of 74 days with 40% of pts demonstrating a Bria-IMT PFS (PFS2) similar to or &gt; their prior line PFS (PFS1). 39% of pts experienced a PFS2 ≥ their most recent line of ADC PFS. The disease control rate was 40% among evaluable pts. 43% of pts had a reduction in cancer-associated macrophage-like cell (CAML) levels; median reduction was 36% (22-98%) after 1 cycle. There were no toxicity-related treatment discontinuations. 43% (10/23) reported grade 3 or 4 AEs, independent of study drug causality. No interstitial lung disease (ILD) reported. AEs included injection site reaction (39%), fatigue (26%), and nausea/vomiting (43%), mostly mild to moderate. One case of elevated lipase was the most clinically significant grade 4 AE. Conclusion: The retrospective analysis of the Bria-IMT™ regimen in ADC refractory MBC patients suggests a potential treatment option for this patient population. The absence of serious AEs, notably ILD, and no toxicity-related treatment discontinuations, underscores the regimen's favorable safety profile. Future studies are warranted to confirm these results and explore the potential of Bria-IMT™ in broader clinical settings. Citation Format: Chaitali Nangia, Carmen Calfa, Blaise Bayer, Mingjin Chang, William Williams, Giuseppe Del Priore, Charles Wiseman, Saranya Chumsri. Efficacy and safety of SV-BR-1-GM after progression on ADC in metastatic breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT206.

Abstract Background: Bria-IMT (SV-BR-1-GM) is an off-the-shelf whole tumor cell therapeutic vaccine engineered to express class I & class II HLAs, secrete GM-CSF, and function as antigen-presenting cells; with subsequent enhancements improving in-vitro characteristics. By expressing cancer antigens such as HER2/Neu and PRAME, SV-BR-1-GM also serves as the reservoir of cancer antigens to activates patient’s anti-tumor immune responses. The safety and efficacy of the ongoing clinical trial of SV-BR-1-GM in combination with a PD1 inhibitor are reported. We also report post-hoc exploratory data for patients with advanced metastatic breast cancer (aMBC) treated with SV-BR-1-GM regimens. Methods: Ongoing prospective, phase 1-2, with an expansion randomized phase 2 cohort (NCT03328026; 2018-present) using SV-BR-1-GM with a PD1 inhibitor (pembrolizumab or retifanlimab) with cycles every 3 weeks (16 patients dosed to date). SV-BR-1-GM “monotherapy” (NCT03066947; 2013-8), a completed prospective phase 1-2 results are also presented. Results: A total of 51 patients received any SV-BR-1-GM regimen; 27 in monotherapy (SV) and 24 in combination with a PD-1 inhibitor (CO) currently ongoing: 4 subjects from SV continued on with CO. Median prior regimens = 5; 61% ER or PR+; 6% ER or PR-/HER2+ and 29% triple negative. SV-BR-1-GM was well tolerated. Disease control rate was 40% with SV and 41% with CO in subjects with available assessment(s). Median PFS was 2.7 months with 6 having PFS &gt;150 days (150-226) for SV and 2.6 months with 5 &gt; 150 days (188-308) for CO. Per protocol, 23 patients had anergy testing prior to treatment. Among those with a normal immunologic response (n=13, 56%), disease outcomes included 4 SD and 2 PR (46% CBR) vs anergic patients (n=7, 30%) with 1 SD (14% CBR); 3 patients (13%) with unknown anergy testing had 0% CBR. All 7 anergic patients developed delayed-type hypersensitivity (DTH) injection site responses to SV-BR-1-GM. Subjects with DTH (injection site induration/erythema) had a significant reduction in the risk of progression or death (HR=0.096, 95%CI:0.02-0.50, p&lt;0.05). Subjects with a reduction in circulating tumor cells (CTC) also had an improvement in PFS (HR 0.08, p=.0012). Median OS (uncensored) was 11.2 months in CO (n = 8). 7 out of 20 (35%) for SV and 9 out of 22 subjects (41%) for CO with available data, exceeded prior PFS. Among HLA matched subjects 4/7 (57%) and 6/9 (67%), respectively, had an increase in PFS. PFS ratio improved independent of prior number of lines, HER2 or HR status. The greatest improvement in PFS on a SV-BR-1-GM was in a HLA matched subject (&gt;6mo). TEAEs occurred in 20/24 (83%) of subjects in CO including 9/24 (38%) with injection site AEs. There were no AEs of special interest eg cytokine storm. There were no Grade 5 and only 6 grade 4 AEs in CO. Conclusions: In an ongoing randomized phase 2, anergic patients had worse outcomes. SV-BR-1-GM was able to illicit an immune response regardless. Responses, stable disease and CBR were seen and associated with immune responses including injection site erythema/induration (DTH), CTC changes and tumor grade I/II. Patients with disease control had better quality of life. SV-BR-1-GM may be able to alter an anergic immune system for clinical benefit. Future pivotal trials will be based upon the ongoing confirmatory randomized clinical trial. Citation Format: Saranya Chumsri, Minal Barve, Chaitali Nangia, Bonnie L. Guerin, Jarrod Holmes, Karim Mohammed, John Knecht, Shaker Dakhil, William V. Williams, Charles Wiseman, Mingjin Chang, Miguel Lopez-Lago, John G. Knecht, Kendrith Rowland, Ralph V. Boccia, Giuseppe Del Priore, Carmen Calfa. Whole cell antigen presenting immune stimulating cells (Bria-IMT) for the treatment of metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT143.

Abstract Background: SV-BR-1-GM is an irradiated allogeneic cell line derived from a hormone receptor-negative (HR-) HER2-positive (HER2+) breast cancer (BC), now engineered to express HLA class I and II antigens, secrete GM-CSF and function as an antigen-presenting cell. Here we report post-hoc exploratory data for metastatic BC (MBC) patients treated with the SV-BR-1-GM regimen (SV) alone (NCT03066947) and in combination (CO) with immune checkpoint inhibitors (ICIs) (NCT03328026). Methods: SV includes cyclophosphamide 300 mg/m2 i.v. 48-72 hours prior to SV-BR-1-GM (20 × 106 cells) intradermally followed by interferon-alpha-2b at the SV-BR-1-GM inoculation sites on days 2 and 4. SV was given every 2 weeks for 3 cycles and then monthly in NCT03066947, and every 3 weeks in combination with PD-1 inhibitors in NCT03328026. Treatment was continued until disease progression or unacceptable toxicities. Results: A total of 34 refractory MBC patients (pts) were treated, including 24 with SV, and 14 with CO, including 4 who crossed over from SV to CO plus one who restarted the SV after a protocol specified administrative interruption in treatment. Median prior regimens were 5; 55% of pts had hormone receptor-positive (HR+) BC, 42% had HER2+ BC, and 16% were triple-negative BC (TNBC). Objective response rates (ORR) were 4% for monotherapy and 7% for combination. Clinical benefit rate (CBR) was 21% for monotherapy and 29% for combination. Responses and clinical benefits were seen across most BC subtypes (see table). Notably, CBR among 10 pts with HR+ BC (any HER2) who received the combination was 50% (5/10). The duration of response (DOR) among 4 patients treated with monotherapy was 49-223 days and DOR among 6 patients treated with combination was 72-292 days. Median PFS was 2.8 months for monotherapy and 4.2 months for combination. Median OS was 7.0 months for monotherapy, and 12.0 months for combination. Of 28 pts with available prior treatment data, 12 (43%) had PFS on study treatment exceeded PFS on prior treatment, of these 8/12 had &gt;1 HLA match and 5/8 had ≥ 2 loci HLA-matched with SV-BR-1-GM. PFS ratio improvement was independent of the prior number of lines of therapy or BC subtypes. The SV-BR-1GM regimen was well tolerated with the most common treatment-related adverse events (AEs) being injection site reaction in 67%. There was no dose-limiting toxicity, special interest AEs such as cytokine storm, and no grade 5 observed. There were 2 non-treatment-related grade 4 AEs: worsening pleural effusion and altered mental status. Significant improvement in PFS was observed in patients with matched HLA and in association with the delayed-type hypersensitivity skin test, peripheral blood circulating tumor cells, and cancer-associated macrophages. Conclusions: SV-BR-1-GM demonstrated promising activity in patients with MBC. Treatment was well tolerated with no concerning AEs. The PFS ratio compares favorably with prior penultimate standards of care, more notably in patients with matched HLA. Clinical benefits were observed across multiple subtypes of BC, particularly in patients with HR+ disease receiving combination therapy. Phase II clinical trial is currently ongoing to evaluate the efficacy of SV-BR-1-GM in combination with ICIs. Clinical benefit and PFS on SV-BR-1-GM SV-BR-1-GM Whole Cell Therapeutic Vaccine in Heavily Pre-Treated Metastatic Breast Cancer Results Stratified by HER2 and HLA Matching Citation Format: Saranya Chumsri, William Williams, Mingjin Chang, Miguel Lopez-Lago, Charles Wiseman, Jarrod Holmes, Chaitali Nangia, Karim Mohammed, Minal Barve, Shaker Dakhil, Bonnie Guerin, Giuseppe Del Priore, Carmen Calfa. Allogeneic, Antigen-Presenting, GM-CSF-secreting, SV-BR-1-GM Whole Cell Therapeutic Vaccine in Advanced Metastatic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-12.