Williams, William V.

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.

Abstract Background: Tumor-associated macrophages have been shown to play a critical role in metastasis, angiogenesis, and immune escape. Cancer associated macrophage-like cells (CAMLs) are circulating stromal cell with macrophage expression subtypes, detected in the peripheral blood of patients with solid tumors. We have previously shown that enlargement of CAML cells is an independent predictor of poorer overall survival and an indication of progression in patients with metastatic breast cancer (MBC). However changes in CAML sizes after induction of therapy has not been investigated. Here we evaluated the association between early changes in numbers and sizes of CAMLs as it relates to clinical response after induction of new therapy. Method: Peripheral blood samples from 29 patients with metastatic breast cancer who failed at least 2 prior lines of therapies were prospectively collected. Baseline (BL) blood samples were taken prior to initiation of a new therapy and the second samples (T1) were taken approximately 30 days after initiation of a new systemic therapy. Blood samples were filtered using CellSieveTM filtration. The quantity and size of CAMLs were measured then compared between the BL and T1 time points. Univariate analysis was used to determine the association of changes in CAML numbers and changes in CAML size, with objective response at the first follow up CT scan with progression free survival (PFS). Results: CAMLs were detected in 97% of BL samples (averaging 20.9 CAMLs/7.5ml blood) and 93% of T1 samples (averaging 18.5 CAMLs/7.5mL blood). At the time of the first follow up CT scan, 17 of 29 patients (58.6%) had progressive disease based on the RECIST criteria. Among those, 14 of 17 patients (82%) had an increase in CAML size (~85% overall enlargement) and 3/17 (18%) had a decrease CAML size (~60% overall shrinkage) in T1 samples compared to baseline. In contrast, 10 of 12 patients (83%) with clinical benefit, including stable disease and partial or complete response, had a 92% reduction in their CAML’s size and 2 of 12 patients (17%) had 61% enlargement in their CAML’s size after treatment. Overall, CAML size change after therapy induction was 83% accurate in predicting clinical benefit based on subsequent scans. Furthermore, patients with enlarging CAML size at T1 had significantly shorter PFS of 4 months compared to 10 months in patients with decreasing CAML size (HR 3.7; 95%CI1.5-10.1; p 0.020). Conclusion: CAMLs can be commonly found in most treatment-refractory metastatic breast cancer patients and their morphological size is clinically correlated to poorer survival. Our data suggests that monitoring the size changes of a patient’s CAMLs after 30 days of new treatment initiation may predict clinical benefit earlier than conventional scans and act as real time monitoring of MBCs response to new therapies. Additional studies are currently ongoing to validate these results. Citation Format: Saranya Chumsri, Markus D. Lacher, William V. Williams, R. K. Alpaugh, Stuart S. Martin, Rena Lapidus, Cha-Mei Tang, Massimo Cristofanilli, Daniel L Adams. Circulating cancer associated macrophage-like cells (CAMLs) are early predictors of response to new line therapies in metastatic breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-06-27.