Williams, William G.

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 .

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 > 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 > 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.

Purpose We reviewed all 64 articles ever published by The Congenital Heart Surgeons’ Society (CHSS) Data Center to estimate the academic impact of these peer-reviewed articles. Materials and Methods The Congenital Heart Surgeons’ Society has performed research based on 12 Diagnostic Inception Cohorts. The first cohort (Transposition) began enrolling patients on January 1, 1985. We queried PubMed to determine the number of publications that referenced each of the 64 journal articles generated by the datasets of the 12 Diagnostic Inception Cohorts that comprise the CHSS Database. Descriptive summaries of the data were tabulated using mean with standard deviation and median with range. Results Sixty-four peer-reviewed papers have been published based on the CHSS Database. Fifty-nine peer-reviewed articles have been published based on the 12 Diagnostic Inception Cohorts, and five additional articles have been published based on Data Science. Excluding the recently established Diagnostic Inception Cohort for patients with Ebstein malformation of tricuspid valve, the number of papers published per cohort ranged from 1 for coarctation to 11 for transposition of the great arteries. The 11 articles generated from the CHSS Transposition Cohort were referenced by a total of 111 articles (median number of references per journal article = 9 [range = 0-22, mean = 10.1]). Overall, individual articles were cited by an average of 11 (mean), and a maximum of 41 PubMed-listed publications. Overall, these 64 peer-reviewed articles based on the CHSS Database were cited 692 times in PubMed-listed publications. The first CHSS peer-reviewed article was published in 1987, and during the 35 years from 1987 to 2022, inclusive, the annual number of CHSS publications has ranged from 0 to 7, with a mean of 1.8 publications per year (median = 1, mode = 1). Conclusion Congenital Heart Surgeons’ Society studies are widely referenced in the pediatric cardiac surgical literature, with over 10 citations per published article. These cohorts provide unique information unavailable in other sources of data. A tool to access this analysis is available at: [ https://data-center.chss.org/multimedia/files/2022/CAI.pdf ].

3056 Background: In metastatic Breast Cancer (mBC), Circulating Tumor Cells (CTCs) are established prognostic indicators of patients (pts) not responding to new lines of therapy and who have poor clinical outcomes. However, CTCs are typically found in < 20% of mBC pts and many pts without CTCs will also progress. Recently an inflammatory pro-tumorigenic macrophage emanating from tumor stroma (i.e. Cancer associated macrophage-like cell [CAML]) was found in > 90% of mBC pts and were also indicative of poor clinical outcomes. As CTCs & CAMLs are isolated in conjunction from a single blood sample, and both are prognostic for therapy response, we evaluated CTCs & CAMLs before and after initiation of new therapies in mBC to determine their combined prognostic/predictive values. Methods: An observational prospective 2-year multi-institutional study was undertaken to evaluate CTCs & CAMLs before, and after, induction of any new line of therapy in pts with diagnosed mBC (n = 101). Anonymized and blinded blood samples were taken at baseline (BL), prior to starting a new systemic therapy, and a 2nd sample (T1) taken after therapy initiation (̃30 days). Blood was filtered by CellSieve filtration. The quantities and subtypes of CTCs & CAMLs were analyzed based on RECIST v1.1 for progression-free survival (PFS) and overall survival (OS) hazard ratios (HRs) by censored univariate & multivariate analysis at 2 years. Results: CTCs were identified in 35% (n = 35/101) of pts at BL & 24% (n = 24/101) at T1, with a single CTC at T1 being highly prognostic for worse PFS HR = 6.2 95%CI 3.0-13.2, p < 0.001 & OS (HR = 5.1 95%CI 2.0-13.4, p = 0.002. In parallel, CAMLs were found in 93% of BL and 86% of T1 samples, and whose decreases were significantly prognostic for improved PFS (HR = 2.7, 95%CI 1.4-5.1, p = 0.006) and OS (HR = 4.4 95%CI 1.5-13.2, p = 0.018) when CTCs were absent. Overall ≥1 CTC at T1 (n = 24) had median PFS = 2.4 & mOS = 4.8 months (mos), however, in pts without CTCs plus an increase in CAMLs (n = 36) had mPFS = 5.9 & mOS = 14.1 mos, while in pts without CTCs plus a decrease in CAMLs (n = 41) had mPFS = 14.8 & mOS = 18.8 mos. Conclusions: Our data confirms that pts with persistent CTCs have the worst clinical outcomes. Further, simultaneous CAML quantification provided a new dynamic predictive blood based biomarker in pts without detectable CTCs which may be useful to better individualize therapy and improve outcomes, though future studies are need to validate these findings.

e14048 Background: Cancer associated macrophage like cells (CAMLs), a circulating stromal cell subtype, has been shown as an independent prognostic indicator of survival in late stage metastatic breast cancer when cells enlarge to ≥50µm. However, no study has evaluated the clinical relationship between changes in CAML size and their ability to predict treatment response. While CAMLs are prognostic for progression, we hypothesized that monitoring changes in CAMLs after initiation of therapy may be predictive for responsiveness of new treatment regimens. Methods: A prospective 12 months blind multi-institutional pilot study was undertaken to evaluate CAMLs before, and after, induction of a new line of investigational therapy based on CT scans. Patients with progressive metastatic breast cancer (n = 29) who had failed at least 2 prior therapies were recruited. A baseline (BL) blood sample was taken prior to induction of a new therapy and a 2nd sample (T1) taken after initiation (~30 days). Blood was filtered by CellSieve filtration.The quantities and sizes of CAMLs were analyzed based on PFS hazard ratios (HRs) by censored univariate analysis. Results: CAMLs were found in 97% of BL samples and 93% of T1 samples. At first CT scan, after the assigned dose of investigational treatment, 17 of 29 patients had clinical progression with 14/17 (82%) patients having an increased CAML size and 3/17 (18%) having a decreased CAML size. The remaining 12 of 29 patients saw clinically stable, or regression, of disease with 10/12 (83%) having decreased CAML size and 2/12 (17%) having increased CAML size. Overall CAML size change after therapy induction was 83% accurate at predicting response or progression based on CT scans. Further, patients with increasing CAML size at T1 had a 4 month mPFS vs 10 month mPFS for decreasing CAMLs, with a lower 12 month PFS HR = 3.7 (95%CI = 1.5-10.1, p = 0.020). Conclusions: Our data suggests that in metastatic breast cancer, monitoring CAMLs changes over the first 30 days of treatment accurately predicts responsiveness of disease to new treatments. Further, we suggests using blood sampling may increase the clinical value of blood based diagnostics by rapidly predicting the benefit of subsequent therapies.