A phase 1b study of safety and immune response to PVX-410 vaccine alone and in combination with durvalumab (MEDI4736) in HLA-A2+ patients following adjuvant therapy for stage 2/3 triple negative breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS1126-TPS1126 ◽  
Author(s):  
Steven J. Isakoff ◽  
Sara M. Tolaney ◽  
Nadine M. Tung ◽  
Sylvia Adams ◽  
Hatem Hussein Soliman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Adjuvant Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Peptide Vaccine ◽  
Rank Test ◽  
Paired Data ◽  
Phase 1B

TPS1126 Background: Stage 2-3 triple negative breast cancer (TNBC) remains at high risk for recurrence despite modern adjuvant therapy. An important role for the immune system in TNBC has recently emerged. Tumor infiltrating lymphocytes (TILs) are correlated with improved prognosis and several PD-1/PD-L1 checkpoint inhibitors, including Durvalumab (DUR), demonstrated activity in metastatic TNBC. Vaccines are a promising approach to further enhance the immune response in many cancers including TNBC. PVX-410 (PVX) is a novel tetra-peptide vaccine against XBP1 (2 splice variants), CD138 and CS1 that was safe and induced immune responses in a phase 1b study in smoldering myeloma. XBP1 and CD138 are also over-expressed in TNBC. Methods: This Phase 1b multi-center, single arm study will enroll 20 HLA-A2+ female patients (pts) following completion of all adjuvant therapy for stage 2-3 TNBC. Pts will receive 6 doses of 800ug PVX (emulsified in Montanide (SC) and co-administered with Hiltonol (IM)) at 2-week intervals, and 2 doses of DUR 1500mg IV at the 4th and 6th vaccine visits. Eligible pts must be between 1-6 months from completing adjuvant therapy, have no prior autoimmune disease, and have residual disease if neoadjuvant therapy was used. The primary objective is to determine the safety and tolerability of the combination, and the key secondary objective is to determine the immune response to PVX + DUR. If ≤1 pt in the first 6 has a protocol defined dose limiting toxicity within 4 weeks after the first DUR dose, accrual will continue to 20 pts. Immune response will be assessed at baseline, pre-dose 4 PVX/dose 1 DUR, and 4 weeks after completing protocol therapy. Paired data in 20 pts provides 90% power to see a shift of 0.75 standardized units from baseline to 4 weeks post treatment with the signed rank test. Immune response will be determined by a FACs based assay of antigen specific CD3+CD8+ T lymphocyte response and IFN-γ production (intracellular staining) in patient PBMCs. Additional correlative studies, including T-cell PD-1 and tissue PD-L1, XBP1, and CD138, are planned. Currently 4 pts are enrolled. Clinical trial information: NCT02826434.

scholarly journals Multi-Gene Testing Overview with a Clinical Perspective in Metastatic Triple-Negative Breast Cancer

2021 ◽  
Vol 22 (13) ◽  
pp. 7154
Author(s):  
Martina Dameri ◽  
Lorenzo Ferrando ◽  
Gabriella Cirmena ◽  
Claudio Vernieri ◽  
Giancarlo Pruneri ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Checkpoint Inhibitors ◽  
Gene Testing ◽  
Repair Deficiency ◽  
Targeted Treatments ◽  
Recombination Repair ◽  
Tumor Mutational Burden ◽  
Next Generation Sequencing Ngs

Next-generation sequencing (NGS) is the technology of choice for the routine screening of tumor samples in clinical practice. In this setting, the targeted sequencing of a restricted number of clinically relevant genes represents the most practical option when looking for genetic variants associated with cancer, as well as for the choice of targeted treatments. In this review, we analyze available NGS platforms and clinical applications of multi-gene testing in breast cancer, with a focus on metastatic triple-negative breast cancer (mTNBC). We make an overview of the clinical utility of multi-gene testing in mTNBC, and then, as immunotherapy is emerging as a possible targeted therapy for mTNBC, we also briefly report on the results of the latest clinical trials involving immune checkpoint inhibitors (ICIs) and TNBC, where NGS could play a role for the potential predictive utility of homologous recombination repair deficiency (HRD) and tumor mutational burden (TMB).

scholarly journals 614 Investigating immune mediated mechanisms of PARPi resistance in BRCA1-associated triple negative breast cancer (TNBC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A644-A644
Author(s):  
Anita Mehta ◽  
Madeline Townsend ◽  
Madisson Oliwa ◽  
Patrice Lee ◽  
Nicholas Saccomano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Flow Cytometry ◽  
Immune Response ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Triple Combination ◽  
Tumor Clearance ◽  
Sting Pathway

BackgroundPoly(ADP-ribose) polymerase inhibitors (PARPi) have improved the outcomes of BRCA-associated breast cancer; however, treatment responses are often not durable. Our preclinical studies demonstrated that PARPi activates the cGAS/STING pathway and recruitment of anti-tumor CD8+ T-cells that are required for tumor clearance [1]. These studies contributed to development of clinical trials testing PARPi plus immune checkpoint blockade (ICB). Unfortunately, early phase trials of PARPi + ICB have not yet suggested efficacy will be superior to PARPi monotherapy. Lack of demonstrated clinical synergy between PARPi + ICB underscores the need to study the tumor microenvironment (TME) during PARPi therapy to identify optimal strategies to enhance T-cell activation. We recently showed that PARPi induces CSF-1R+ suppressive tumor associated macrophages (TAMs) that restrict antitumor immune responses, contributing to PARPi resistance [2]. Removing TAMs with anti-CSF-1R therapy in combination with PARPi significantly enhanced overall survival (OS) compared to PARPi monotherapy in preclinical models [2]. Here, we investigate how modulating TAMs can enhance PARPi + ICB.MethodsMice bearing BRCA1-deficient TNBC (K14-Cre;Brca1f/f;p53f/f) tumors were treated for 98 days with PARPi (Talazoparib) ± small molecule inhibitor of CSF-1R (ARRAY-382; CSF-1Ri) ± anti-PD-1 and then followed for survival. Flow cytometry was employed to elucidate changes in the TME after treatment.ResultsPARPi conferred a significant survival advantage over vehicle treated mice (median OS 33 v. 14 days; p=0.0034) and 2/8 PARPi-treated mice experienced complete tumor clearance at day 98. PARPi + CSF-1Ri treated mice (median OS 140 days) remarkably cleared 7/10 tumors by day 98. The addition of anti-PD-1 to PARPi did not enhance OS compared to PARPi monotherapy. The triple combination of anti-PD-1 + PARPi + CSF-1Ri has not yet significantly enhanced the median OS compared to PARPi + CSF-1Ri (ongoing; 168 v. 140 days); nor did it increase clearance of tumor by day 98 (7/10). However, the triple combination led to superior long term tumor clearance. At day 161 the triple combination exhibited 5/10 tumor free mice compared to 2/10 treated with PARPi + CSF-1Ri. To elucidate how CSR-1Ri enhanced PARPi + ICB responses, flow cytometry was performed and revealed increased expression of the co-stimulatory molecule CD80, reduced tissue resident macrophages (CX3CR1+) and lower CSF-1R expression compared to PARPi + ICB.ConclusionsThese data suggest that targeting immunosuppressive macrophages may induce a favorable anti-tumor immune response and enhance responses to PARPi plus ICB. We are currently evaluating the adaptive immune response in this context.ReferencesPantelidou, C., et al., PARP inhibitor efficacy depends on CD8+ T cell recruitment via intratumoral STING pathway activation in BRCA-deficient models of triple-negative breast cancer. Cancer Discovery, 2019: p. CD-18-1218.Mehta, A.K., et al., Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer, 2021. 2(1): p. 66–82.

scholarly journals Epigenetic Regulation of Immunotherapy Response in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4139
Author(s):  
Pere Llinàs-Arias ◽  
Sandra Íñiguez-Muñoz ◽  
Kelly McCann ◽  
Leonie Voorwerk ◽  
Javier I. J. Orozco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Regulatory Elements ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Cancer Subtypes

Triple-negative breast cancer (TNBC) is defined by the absence of estrogen receptor and progesterone receptor and human epidermal growth factor receptor 2 (HER2) overexpression. This malignancy, representing 15–20% of breast cancers, is a clinical challenge due to the lack of targeted treatments, higher intrinsic aggressiveness, and worse outcomes than other breast cancer subtypes. Immune checkpoint inhibitors have shown promising efficacy for early-stage and advanced TNBC, but this seems limited to a subgroup of patients. Understanding the underlying mechanisms that determine immunotherapy efficiency is essential to identifying which TNBC patients will respond to immunotherapy-based treatments and help to develop new therapeutic strategies. Emerging evidence supports that epigenetic alterations, including aberrant chromatin architecture conformation and the modulation of gene regulatory elements, are critical mechanisms for immune escape. These alterations are particularly interesting since they can be reverted through the inhibition of epigenetic regulators. For that reason, several recent studies suggest that the combination of epigenetic drugs and immunotherapeutic agents can boost anticancer immune responses. In this review, we focused on the contribution of epigenetics to the crosstalk between immune and cancer cells, its relevance on immunotherapy response in TNBC, and the potential benefits of combined treatments.

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