Holmes, Jarrod P.

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 >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 > 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: 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 >150 days (150-226) for SV and 2.6 months with 5 > 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<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 (>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 >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.