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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited treatment options, which warrants the identification of novel therapeutic targets. Deciphering nuances in the tumor microenvironment (TME) may unveil insightful links between anti-tumor immunity and clinical outcomes, yet such connections remain underexplored. Here we employed a dataset derived from imaging mass cytometry of 71 TNBC patient specimens at single-cell resolution and performed in-depth quantifications with a suite of multi-scale computational algorithms. The TNBC TME reflected a heterogeneous ecosystem with high spatial and compositional heterogeneity. Spatial analysis identified ten recurrent cellular neighborhoods (CNs) - a collection of local TME characteristics with unique cell components. The prevalence of CNs enriched with B cells, fibroblasts, and tumor cells, in conjunction with vascular density and perivasculature immune profiles, could significantly enrich for long-term survivors. Furthermore, relative spatial colocalization of SMA hi fibroblasts and tumor cells compared to B cells correlated significantly with favorable clinical outcomes. Using a deep learning model trained on engineered spatial data, we can predict with high accuracy (mean AUC of 5-fold cross-validation = 0.71) how a separate cohort of patients in the NeoTRIP clinical trial will respond to treatment based on baseline TME features. These data reinforce that the TME architecture is structured in cellular compositions, spatial organizations, vasculature biology, and molecular profiles, and suggest novel imaging-based biomarkers for treatment development in the context of TNBC., (Copyright © 2024. Published by Elsevier Inc.)

Patients with metastatic triple-negative breast cancer (TNBC) show variable responses to PD-1 inhibition. Efficient patient selection by predictive biomarkers would be desirable but is hindered by the limited performance of existing biomarkers. Here, we leveraged in silico patient cohorts generated using a quantitative systems pharmacology model of metastatic TNBC, informed by transcriptomic and clinical data, to explore potential ways to improve patient selection. We evaluated and quantified the performance of 90 biomarker candidates, including various cellular and molecular species, at different cutoffs by a cutoff-based biomarker testing algorithm combined with machine learning-based feature selection. Combinations of pretreatment biomarkers improved the specificity compared to single biomarkers at the cost of reduced sensitivity. On the other hand, early on-treatment biomarkers, such as the relative change in tumor diameter from baseline measured at two weeks after treatment initiation, achieved remarkably higher sensitivity and specificity. Further, blood-based biomarkers had a comparable ability to tumor- or lymph node-based biomarkers in identifying a subset of responders, potentially suggesting a less invasive way for patient selection., Competing Interests: Competing interests statement:L.A.E. has served as a paid consultant for F. Hoffmann-La Roche, Genentech, Macrogenics, Lilly, Chugai, Silverback, Shionogi, CytomX, GPCR, Immunitas, DNAMx, Gilead, Mersana, Immutep, and BioLineRx. L.A.E. also has an executive role at the Society for Immunotherapy of Cancer and has ownership interest in MolecuVax. L.A.E. is a former employee of Ankyra Therapeutics with the potential for future stock options. E.M.J. reports personal fees from Genocea, Achilles, DragonFly, Candel Therapeutics, Carta, NextCure. E.M.J. has had other support from Abmeta, the Parker Institute, and grants and other support from Lustgarten, Genentech, AstraZeneca, and Break Through Cancer outside of the submitted work. E.J.F. is on the Scientific Advisory Board of Viosera Therapeutics/Resistance Bio and is a consultant to Mestag Therapeutics. C.A.S.-M. has research funding from Pfizer, AstraZeneca, Merck, GSK/Tesaro, Novartis, and Bristol Myers Squibb and has served on advisory boards for Bristol Myers Squibb, Merck, Genomic Health, Seattle Genetics, Athenex, Halozyme, and Polyphor. A.S.P. is a consultant to Incyte, J&J/Janssen, and is co-founder and consultant to AsclepiX Therapeutics; he receives research funding from Merck. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.

Cancer immunotherapy has flourished over the last 10-15 years, transforming the practice of oncology and providing long-term clinical benefit to some patients. During this time, three distinct classes of immune checkpoint inhibitors, chimeric antigen receptor-T cell therapies specific for two targets, and two distinct classes of bispecific T cell engagers, a vaccine, and an oncolytic virus have joined cytokines as a standard of cancer care. At the same time, scientific progress has delivered vast amounts of new knowledge. For example, advances in technologies such as single-cell sequencing and spatial transcriptomics have provided deep insights into the immunobiology of the tumor microenvironment. With this rapid clinical and scientific progress, the field of cancer immunotherapy is currently at a critical inflection point, with potential for exponential growth over the next decade. Recognizing this, the Society for Immunotherapy of Cancer convened a diverse group of experts in cancer immunotherapy representing academia, the pharmaceutical and biotechnology industries, patient advocacy, and the regulatory community to identify current opportunities and challenges with the goal of prioritizing areas with the highest potential for clinical impact. The consensus group identified seven high-priority areas of current opportunity for the field: mechanisms of antitumor activity and toxicity; mechanisms of drug resistance; biomarkers and biospecimens; unique aspects of novel therapeutics; host and environmental interactions; premalignant immunity, immune interception, and immunoprevention; and clinical trial design, endpoints, and conduct. Additionally, potential roadblocks to progress were discussed, and several topics were identified as cross-cutting tools for optimization, each with potential to impact multiple scientific priority areas. These cross-cutting tools include preclinical models, data curation and sharing, biopsies and biospecimens, diversification of funding sources, definitions and standards, and patient engagement. Finally, three key guiding principles were identified that will both optimize and maximize progress in the field. These include engaging the patient community; cultivating diversity, equity, inclusion, and accessibility; and leveraging the power of artificial intelligence to accelerate progress. Here, we present the outcomes of these discussions as a strategic vision to galvanize the field for the next decade of exponential progress in cancer immunotherapy., Competing Interests: Competing interests: LAE, employee, Ankyra Therapeutics; researcher, AbbVie, AstraZeneca, Bolt Therapeutics, Bristol Meyers Squibb, Compugen, Corvus, CytomX, EMD Serono, Genentech, F Hoffman La Roche, Immune Onc, Merck, Next Cure, Silverback, Takeda, and Tempest; consultant/advisor/speaker, AstraZeneca, BioLineRx, DNAMx, Genentech, F Hoffman La Roche, GPCR, Gilead, Immune Onc, Immunitas, Immutep, Lilly, Macrogenics, Mersana, and Shionogi; royalty and patent beneficiary, potential for royalties in the future from Molecuvax; publicly traded stocks, potential for stock options in the future from Ankyra Therapeutics; Other, NSABP Foundation, Translational Breast Cancer Research Consortium, Breast Cancer Research Foundation, NCI, Department of Defense, Johns Hopkins University, University of California San Francisco, Cornell University, Dana-Farber Cancer Institute, and Stand Up to Cancer. These are grants from non-industry entities. TCB, advisory board, Kalivir, Tabby; consultant, Galvanize, Attivare, Mestag, and Tallac. CMC, consultant/advisor/speaker, Bayer, Elephas, Novartis, Nektar Therapeutics, and WiCell Research Institute. ACA, member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, Excepgen, and ImmuneOncia, which have interests in cancer immunotherapy. ACA is also a paid consultant for iTeos Therapeutics and Larkspur Biosciences. ACA is an inventor on patents related to the checkpoint receptor Tim-3. DC, executive role, ORIEN Patient Advisory Council. JLG, royalty and patent beneficiary, Bethesda Handbook of Clinical Oncology (royalty) and UpToDate (royalty); JITC interim editor-in-chief. PH, consultant/advisor/speaker, Dragonfly SAB and Immatics SAB. ADP, researcher, Astellas; consultant/advisor/speaker, ImmunoACT, Stromatis Pharma, GO Therapeutics, Astellas, and MaxCyte. PJR, employee, Novigenix and SA; researcher, Roche, pRED, Schilieren, and CH; consultant/advisor/speaker, Enterome, Transgene, and Maxivax. AWS, researcher, Biohaven Pharmaceuticals, Replimune, Morphogenesis, Shattuck Laboratories, Regeneron, and Merck; consultant/advisor/speaker, InStil Bio, Signatera, Merck, and Regeneron; royalty and patent beneficiary, UpToDate; and publicly traded stocks, Illumina. JAW reports compensation for speaker’s bureau and honoraria from PeerView and serves as a consultant and/or advisory board member for Gustave Roussy Cancer Center, EverImmune, OSE Immunotherapeutics, Bayer Therapeutics, James Cancer Center OSU, Daiichi Sanyko. SITC staff: EG, nothing to disclose. JW, nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents., Experimental Design: This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1)., Results: A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA., Conclusions: TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers., Significance: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Invasive cancers typically evade immune surveillance through profound local and systemic immunosuppression, preventing their elimination or control. Targeting immune interventions to prevent or intercept premalignant lesions, before significant immune dysregulation has occurred, may be a more successful strategy. The field of cancer immune interception and prevention is nascent, and the scientific community has been slow to embrace this potentially most rational approach to reducing the global burden of cancer. This may change due to recent promising advances in cancer immunoprevention including the use of vaccines for the prevention of viral cancers, the use of cancer-associated antigen vaccines in the setting of precancers, and the development of cancer-preventative vaccines for high-risk individuals who are healthy but carry cancer-associated heritable genetic mutations. Furthermore, there is increasing recognition of the importance of cancer prevention and interception by national cancer organizations. The National Cancer Institute (NCI) recently released the National Cancer Plan, which includes cancer prevention among the top priorities of the institute. The NCI's Division of Cancer Prevention has been introducing new funding opportunities for scientists with an interest in the field of cancer prevention: The Cancer Prevention-Interception Targeted Agent Discovery Program and The Cancer Immunoprevention Network. Moreover, the Human Tumor Atlas Network is spearheading the development of a precancer atlas to better understand the biology of pre-invasive changes, including the tissue microenvironment and the underlying genetics that drive carcinogenesis. These data will inform the development of novel immunoprevention/immuno-interception strategies. International cancer foundations have also started recognizing immunoprevention and immune interception with the American Association for Cancer Research, Cancer Research UK and the Society for Immunotherapy of Cancer each implementing programming focused on this area. This review will present recent advances, opportunities, and challenges in the emerging field of cancer immune prevention and immune interception., Competing Interests: Competing interests: SES—Institutional research support: IMV Inc; Consulting fees: Margenza, Stanford Burnham Prebys. PEC—Nothing to disclose. OJF—Consulting fees: PDS Biotech, GeoVax, Invectys, Inc, Ardigen. SS—Nothing to disclose. LAE—Consulting Fees: F. Hoffmann-La Roche, Genentech, Macrogenics, Lilly, Chugai, Silverback, Shionogi, CytomX, GPCR, Immunitas, DNAMx, Gilead, Mersana, Immutep, BioLineRx; Research funding: Genentech, F. Hoffmann-La Roche, EMD Serono, Merck, AstraZeneca, Takeda, Tempest, Bolt, Silverback, CytomX, Compugen, AbbVie, BMS, NextCure, Immune-Onc; Ownership interest: MolecuVax; Other: Executive role at the Society for Immunotherapy of Cancer; Employment: Ankyra Therapeutics with potential for equity. MD, TH, OK, LW—nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Among new treatment approaches for patients with cancer, few have accelerated as quickly as neoadjuvant immune checkpoint blockade (ICB). Neoadjuvant cancer therapy is administered before curative-intent surgery in treatment-naïve patients. Conventional neoadjuvant chemotherapy and radiotherapy are primarily intended to reduce tumor size, improving surgical resectability. However, recent scientific evidence outlined here suggests that neoadjuvant immunotherapy can expand and transcriptionally modify tumor-specific T cell clones to enhance both intratumoral and systemic anti-tumor immunity. It further offers a unique "window of opportunity" to explore mechanisms and identify novel biomarkers of ICB response and resistance, opening possibilities for refining long-term clinical outcome predictions and developing new, more highly effective ICB combination therapies. Here, we examine advances in clinical and scientific knowledge gleaned from studies in select cancers and describe emerging key principles relevant to neoadjuvant ICB across many cancer types., Competing Interests: Declaration of interests SLT and DMP receive consulting fees from Bristol Myers Squibb, Compugen, Dragonfly Therapeutics, Janssen Pharmaceuticals, PathAI, Regeneron, and Tizona LLC; receive research grants from Bristol Myers Squibb and Compugen; have stock options or stock in Dragonfly Therapeutics and Tizona LLC; and have patents related to T cell regulatory molecules including LAG-3, and the treatment of MSI-high cancers with anti-PD-1. PMF receives consulting fees from Amgen, AstraZeneca, BMS, Daiichi, Flame, Fosun, F-Star, G1, Genentech, Janssen, Iteos, Merck, Sanofi, Novartis, Regeneron, Surface, Synthekine, Tavotek, Teva; receives research grants from AstraZeneca, BMS, BioNTech, Novartis, and Regeneron; and has a patent related to the use of persistent mutation burden to predict benefit from immunotherapy in solid tumors. LAE is a current employee of Ankyra Therapeutics, with potential for future stock options; is the current President for the Society for Immunotherapy of Cancer; has received research funding to the institution for clinical research work sponsored by Abbvie, AstraZeneca, Bristol Myers Squibb, Compugen, CytomX, EMD Serono, Roche/Genentech, Immune Onc, Merck, Next Cure, Silverback Therapeutics, Takeda, and Tempest; acknowledges a consulting/advisory activity for AstraZeneca, Chugai, CytomX, Roche/Genentech, Gilead, GPCR, Immune Onc, Immutep, Mersana, and Shionogi; acknowledges Roche/Genentech for medical writing support; and has the potential for future stock options from Molecuvax. MY receives consulting fees Genentech/Roche, Exelixis, Eisai, AstraZeneca, Replimune, and Hepion; receives research grants from Bristol Myers Squibb, Incyte, and Genentech/Roche; and has equity interest in Adventris Pharmaceuticals. KNS has received honoraria/consulting fees from Adaptive Biotechnologies; receives research funding from BMS, Abbvie, AstraZeneca, and Enara; holds founder’s equity in ManaT Bio, Inc.; and has filed for patent protection related to the MANAFEST technology and T cell receptors specific for neoantigens derived from recurrent mutant oncogenes., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC), a highly metastatic breast cancer subtype, has limited treatment options. While a small number of patients attain clinical benefit with single-agent checkpoint inhibitors, identifying these patients before the therapy remains challenging. Here, we developed a transcriptome-informed quantitative systems pharmacology model of metastatic TNBC by integrating heterogenous metastatic tumors. In silico clinical trial with an anti-PD-1 drug, pembrolizumab, predicted that several features, such as the density of antigen-presenting cells, the fraction of cytotoxic T cells in lymph nodes, and the richness of cancer clones in tumors, could serve individually as biomarkers but had a higher predictive power as combinations of two biomarkers. We showed that PD-1 inhibition neither consistently enhanced all antitumorigenic factors nor suppressed all protumorigenic factors but ultimately reduced the tumor carrying capacity. Collectively, our predictions suggest several candidate biomarkers that might effectively predict the response to pembrolizumab monotherapy and potential therapeutic targets to develop treatment strategies for metastatic TNBC.

Predictive biomarker testing on metastatic breast cancer is essential for determining patient eligibility for targeted therapeutics. The National Comprehensive Cancer Network currently recommends assessment of specific biomarkers on metastatic tumor subtypes, including hormone receptors, HER2, and BRCA1/2 mutations, on all newly metastatic breast cancers subtypes; programmed death-ligand 1 on metastatic triple-negative carcinomas; and PIK3CA mutation status on estrogen receptor-positive carcinomas. In select circumstances mismatch repair protein deficiency and/or microsatellite insufficiency, tumor mutation burden, and NTRK translocation status are also testing options. Novel biomarker testing, such as detecting PIK3CA mutations in circulating tumor DNA, is expanding in this rapidly evolving arena., Competing Interests: Disclosure G. Jagannathan: None; M.J. White: None; R.R. Xian: None; L.A. Emens: honoraria from AbbVie, Amgen, Celgene, Chugai, GCPR, Gilead, Gritstone, MedImmune, Peregrine, Shionogi, and Syndax; honoraria and travel support from AstraZeneca, Bayer, MacroGenics, Replimune, and Vaccinex; travel support from Bristol Myers Squibb, Genentech/Roche, and Novartis; potential future stock from Molecuvax; institutional support from AbbVie, Aduro Biotech, AstraZeneca, the Breast Cancer Research Foundation, Bristol Myers Squibb, Bolt Therapeutics, Compugen, Corvus, CyTomX, the US Department of Defense, EMD Serono, Genentech, Maxcyte, Merck, the National Cancer Institute, the NSABP Foundation, SU2C, Silverback, Roche, the Translational Breast Cancer Research Consortium, Takeda, Tempest, and HeritX; royalties from Aduro Biotech; A. Cimino-Mathews: Research grants to institution from Bristol-Myers Squibb; consultancy/honoraria to self from Bristol-Myers Squibb and Roche., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Advanced gynecologic cancers have historically lacked effective treatment options. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration for the treatment of cervical cancer and endometrial cancer, offering durable responses for some patients. In addition, many immunotherapy strategies are under investigation for the treatment of earlier stages of disease or in other gynecologic cancers, such as ovarian cancer and rare gynecologic tumors. While the integration of ICIs into the standard of care has improved outcomes for patients, their use requires a nuanced understanding of biomarker testing, treatment selection, patient selection, response evaluation and surveillance, and patient quality of life considerations, among other topics. To address this need for guidance, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline. The Expert Panel drew on the published literature as well as their own clinical experience to develop evidence- and consensus-based recommendations to provide guidance to cancer care professionals treating patients with gynecologic cancer., Competing Interests: Competing interests: SFA – Contracted Research: Astra Zeneca. JB – Contracted Research: (institutional financial interests for conducted research) Eli Lilly, Novartis, Roche, Samsung Bioepis co. Ltd, Sun Pharma, Paxman Coolers. MOB – Consulting Fees: Bristol-Myers Squibb, EMD Serono, GSK, Immunocore, Immunovaccine, Merck & Co., Novartis, Sanofi-Genzyme, Turnstone Biologics, Sun Pharma; Contracted Research: Merck, Takara Bio. TJC – Consulting Fees: Agenus, Xencor; Ownership Interest less than 5%: Agenus, Xencor. MLD – Fees for non-CE services: PER; Contracted Research: Pfizer, EMD Serono, Bavarian Nordisk, Precigen, Epithany, Veanna; Other: Editor-in-Chief, JAMA Oncology; Other Details: Compensation by JAMA. LD – Consulting: Pfizer. LAE – Consulting Fees: Genentech, F Hoffman La Roche, Chugai, GPCR, Gilead, Immune Onc, Immutep, Shionogi, Mersana; Consulting (no fees): Immutep; Contracted Research: Abbvie, Astrazeneca, Bolt Therapeutics, Bristol Myers Squibb, Compugen, Corvus, CytomX, EMD Serono, Genentech, F Hoffman La Roche, Immune Onc, Maxcyte, Merck, Next Cure, Silverback, Takeda, Tempest; Other: HeritX Incorporated, NSABP Foundation, Translational Breast Cancer Research Consortium, Breast Cancer Research Foundation, National Cancer Institute, Department of Defense, Johns Hopkins University, University of California San Francisco, Cornell University, Dana Farber Cancer Institute, Stand Up to Cancer (these are grants from non-industry entities). CFF – Consulting Fees: Bristol-Myers Squibb, Arch Oncology, Seagen, Aptitude Health, OncLive, Aadi Biosciences/GOG Partners; Contracted Research: Genentech/Roche, Astra Zeneca, Bristol Meyers Squibb, Merck, Daiichi; Other: Merck, Genentech; Other Details: Scientific Advisory Board member (compensation waived). MEG – Consulting Fees: SeaGen (Tucatinib). MAG – Researcher: Fate Therapeutics, HCW Biologics; Consultant Advisor Speaker: Merck; NPI: 1265466809. AAJ – Consulting Fees: Nuprobe, Avenge Bio, BMS, Agenus, Instil Bio, GLG, Guidepoint, Macrogenics, Immune-Onc, Alkermes, EMD-Serono, Neo TILs, Genentech-Roche; Contracted Research: Iovance, AstraZeneca, BMS, Merck, Eli Lilly, Xencor, Immatics, Pfizer; Ownership Interest less than 5%: Avenge Bio. JBL – Contracted Research: Merck, Sanofi, AstraZeneca, Laekna, Sumitomo Dainippon Pharma Oncology, Harpoon Therapeutics, Precigen, Forty Seven. HM – Contracted Research: Puma Biotechnology. KO – Salary: The University of Chicago; IP Rights: PCT/US2014025673 “compositions and methods for use of recombinant T cell receptors for direct recognition of tumor antigen, PCT/US2014025456“ enhancement of vaccines; Consulting Fees: GOG Foundation/Celsion, GSK, Dailchi-Sanyo; Contracted Research: Astra Zeneca research funding (grant), Tessaro Pharma research funding (grant). EZ – NPI: 1598921181. SAD, KCK, AM, VSJ – Nothing to disclose. SITC Staff – EG, AK, NL, SMW – Nothing to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immunotherapy, particularly agents targeting the immunoregulatory PD-1/PD-L1 axis, harnesses the power of the immune system to treat cancer, with unique potential for a durable treatment effect due to immunologic memory. The PD-1 inhibitor pembrolizumab combined with neoadjuvant chemotherapy followed by adjuvant pembrolizumab improves event-free survival and is a new standard of care for high-risk, early-stage triple-negative breast cancer (TNBC), regardless of tumor PD-L1 expression. For metastatic TNBC, pembrolizumab combined with chemotherapy is a new standard of care for the first-line therapy of PD-L1 + metastatic TNBC, with improvement in overall survival. The PD-L1 inhibitor atezolizumab combined with nab-paclitaxel is also approved outside the United States for the first-line treatment of metastatic PD-L1 + TNBC. Current research focuses on refining the use of immunotherapy in TNBC by defining informative predictive biomarkers, developing immunotherapy in early and advanced HER2-driven and luminal breast cancers, and overcoming primary and secondary resistance to immunotherapy through unique immune-based strategies., (Copyright © 2023 Cold Spring Harbor Laboratory Press; all rights reserved.)

Background: Veliparib is a poly-ADP-ribose polymerase (PARP) inhibitor, and it has clinical activity with every 3 weeks carboplatin and paclitaxel. In breast cancer, weekly paclitaxel is associated with improved overall survival. We aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of veliparib with weekly carboplatin and paclitaxel as well as safety, pharmacokinetics, and preliminary clinical activity in triple negative breast cancer (TNBC)., Methods: Patients with locally advanced/metastatic solid tumors and adequate organ function were eligible. A standard 3 + 3 dose-escalation design was followed by a TNBC expansion cohort. Veliparib doses ranging from 50 to 200 mg orally bid were tested with carboplatin (AUC 2) and paclitaxel (80 mg/m 2 ) given weekly in a 21-day cycle. Adverse events (AE) were evaluated by CTCAE v4.0, and objective response rate (ORR) was determined by RECIST 1.1., Results: Thirty patients were enrolled, of whom 22 had TNBC. Two dose-limiting toxicities were observed. The RP2D was determined to be 150 mg PO bid veliparib with weekly carboplatin and paclitaxel 2 weeks on, 1 week off, based on hematologic toxicity requiring dose reduction in the first 5 cycles of treatment. The most common grade 3/4 AEs included neutropenia, anemia, and thrombocytopenia. PK parameters of veliparib were comparable to single-agent veliparib. In 23 patients with evaluable disease, the ORR was 65%. In 19 patients with TNBC with evaluable disease, the ORR was 63%., Conclusion: Veliparib can be safely combined with weekly paclitaxel and carboplatin, and this triplet combination has promising clinical activity., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The current standard of care for resected early-stage triple negative breast cancer (TNBC) patients who did not receive systemic preoperative therapy is adjuvant anthracycline- and taxane-based chemotherapy (CT). A network meta-analysis (NMA) of randomized controlled trials (phase III) enrolling patients with resected stage I-III TNBC comparing adjuvant regimens was performed. Overall survival (OS) and disease-free survival (DFS) data were extracted. A total of 27 phase III clinical trials were selected including 15,242 TNBC patients. This NMA showed an OS benefit from the incorporation of capecitabine into classic anthracycline/taxane-based combinations compared to anthracyclines with or without taxanes alone., Competing Interests: Declaration of competing interest None declared., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8 + cytotoxic T lymphocyte (CTL) responses compared with anti-PD-L1 alone. Circulating CTLs from cancer patients with high plasma IL-6 display a repressed functional profile based on single-cell RNA sequencing, and IL-6-STAT3 signaling inhibits classical cytotoxic differentiation of CTLs in vitro. In tumor-bearing mice, CTL-specific IL6R deficiency is sufficient to improve anti-PD-L1 activity. Thus, based on both clinical and experimental evidence, agents targeting IL-6 signaling are plausible partners for combination with ICIs in cancer patients., Competing Interests: Declaration of interests M.A.H., K.Y., L.W., J.E.K., L.L., Y.L., V.G., C.L., D.R., C.O., S.M., S.K., Y.J.C., J.P., Y.S., Z.M., B.B., E.J.F., N.L., H.K., J.Z., M.F., P.W., M.W., I.M., S.J.T., M.M., S.M., L.M., and N.R.W. are employees of Genentech, Inc. M.A.H., K.Y., L.W., J.E.K., L.L., Y.L., P.W., M.M., S.M., L.M., and N.R.W. are inventors on patents related to IL-6. P.S.H. is an employee of Foundation Medicine Inc. K.H. is an employee of Roche Products Ltd. D.F.M. reports a consulting/advisory role for Bristol-Myers Squibb, Merck, Roche/Genentech, Pfizer, Exelixis, Novartis, Eisai, X4 Pharmaceuticals, and Array BioPharma; he also reports that his home institution receives research funding from Prometheus Laboratories. T.P. reports honoraria and consulting/advisory roles with Roche/Genentech, Bristol-Myers Squibb, and Merck; consulting/advisory role with AstraZeneca and Novartis; research funding from AstraZeneca/MedImmune and Roche/Genentech; and other relationships with Ipsen and Bristol-Myers Squibb. L.E. reports honoraria from or consulting/advisory roles with AbbVie, Amgen, AstraZeneca, Bayer, Bristol Meyers Squibb, Celgene, Chugai, eTHeRNA, Genentech, Gritstone, Medimmune, Molecuvax, Macrogenics, Novartis, Peregrine, Replimune, Roche, Silverback, Syndax, and Vaccinex; she reports that her home institution receives funding from Aduro Biotech, AstraZeneca, Breast Cancer Research Foundation, Bristol Meyers Squibb, Corvus, Department of Defense, EMD Serono, Genentech, HeritX, Inc., Maxcyte, Merck, National Cancer Institute, NSABP Foundation, Roche, Tempest, Translational Breast Cancer Research Consortium. J.E.R. has received non-financial support from Roche Genentech and consulting fees from Agensys, Eli Lilly, Sanofi, and Oncogene., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The broad activity of agents blocking the programmed cell death protein 1 and its ligand (the PD-(L)1 axis) revolutionized oncology, offering long-term benefit to patients and even curative responses for tumors that were once associated with dismal prognosis. However, only a minority of patients experience durable clinical benefit with immune checkpoint inhibitor monotherapy in most disease settings. Spurred by preclinical and correlative studies to understand mechanisms of non-response to the PD-(L)1 antagonists and by combination studies in animal tumor models, many drug development programs were designed to combine anti-PD-(L)1 with a variety of approved and investigational chemotherapies, tumor-targeted therapies, antiangiogenic therapies, and other immunotherapies. Several immunotherapy combinations improved survival outcomes in a variety of indications including melanoma, lung, kidney, and liver cancer, among others. This immunotherapy renaissance, however, has led to many combinations being advanced to late-stage development without definitive predictive biomarkers, limited phase I and phase II data, or clinical trial designs that are not optimized for demonstrating the unique attributes of immune-related antitumor activity-for example, landmark progression-free survival and overall survival. The decision to activate a study at an individual site is investigator-driven, and generalized frameworks to evaluate the potential for phase III trials in immuno-oncology to yield positive data, particularly to increase the number of curative responses or otherwise advance the field have thus far been lacking. To assist in evaluating the potential value to patients and the immunotherapy field of phase III trials, the Society for Immunotherapy of Cancer (SITC) has developed a checklist for investigators, described in this manuscript. Although the checklist focuses on anti-PD-(L)1-based combinations, it may be applied to any regimen in which immune modulation is an important component of the antitumor effect., Competing Interests: Competing interests: MBA—Consulting Fees: Aveo, BMS, Eisai, Exelixis, Genentech, Iovance, Merck, Novartis, Pfizer, Roche, Pyxis, Werewolf, Asher Bio, Calithera, Idera, Agenus, Apexigen, Neoleukin, Adagene, AstraZeneca, Elpis, ScholarRock, Surface, ValoHealth, Sanofi, Fathom; Ownership Interest (less than 5%): Werewolf, Pyxis, Elpis. HA-S—Nothing to disclose. PAA—Consulting Fees: BMS, Roche, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTEOS, Medicenna; Contracted Research: BMS, Roche-Genentech, Array, Sanofi. MRB—Consulting Fees: Novartis, Kite/Gilead, CRISPR Therapeutics, Autolus, Takeda, Agios, Iovance, Bluebird Bio, BMS; Fees for Non-CE Services: Agio, BMS, Incyte, Sanofi, Kite/Gilead; Contracted Research: Immatics, Novartis, Kite/Gilead, CRISPR Therapeutics, Autolus, TMUNITY. DSC—Ownership Interest (less than 5%): IGM Biosciences, Corvus. MD—Consulting Fees: Lava Therapeutics, Amgen, Janssen, Roche/Genentech. LAE—Consulting Fees: Genentech, F. Hoffmann-La Roche, Chugai, GPCR, Gilead, Immune Onc, Immutep, Shionogi, Mersana; Contracted Research: AbbVie, AstraZeneca, Bolt Therapeutics, Bristol Myers Squibb, Compugen, Corvus, CytomX, EMD Serono, Genentech, F. Hoffmann-La Roche, ImmuneOnc, Maxcyte, Merck, Next Cure, Silverback, Takeda, Tempest; Grants from Non-Industry Entities: HeritX Incorporated, NSABP Foundation, Translational Breast Cancer Research Consortium, Breast Cancer Research Foundation, National Cancer Institute, Department of Defense, Johns Hopkins University, University of California San Francisco, Cornell University, Dana Farber Cancer Institute. Royalties: Elsevier; IP Rights: Aduro Biotech. MSE—Nothing to Disclose. RLF—Consulting Fees: Achilles Therapeutics, Aduro Biotech, Bicara Therapeutics, BMS, Brooklyn Immunotherapeutic, Everest Clinical Research Corporation, F. Hoffman-La Roche, Genocea Biosciences, Hookipa Biotech GmbH, Instill Bio, Kowa Research Institute, Lifescience Dynamics Limited, MacroGenics, Merck, Mirati Therapeutics, Nanobiotix, Novasenta, Numab Therapeutics AG, OncoCyte Corporation, Pfizer, PPD Development, L.P., Rakuten Medical, Sanofi, Seagen, Vir Biotechnology, Zymeworks; Contracted Research: AstraZeneca/MedImmune, BMS, Merck, Novasenta, Tesaro; Stock: Novasenta. TFG—Contracted Research: AstraZeneca, BMS, Merck, Sillajen, Vascular Biogenics. JLG—Nothing to disclose. RSH—Consulting Fees: AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Bayer HealthCare Pharmaceuticals, Bolt Biotherapeutics, BMS, Candel Therapeutics, Cybrexa Therapeutics, eFFECTOR Therapeutics, Eli Lilly and Company, EMD Serono, Foundation Medicine, Genentech/Roche, Genmab, Gilead, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Loxo Oncology, Merck and Company, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Ocean Biomedical, Oncternal Therapeutics, Pfizer, Ribbon Therapeutics, Ventana Medical Systems, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Symphogen, Takeda, Tesaro, Tocagen, WindMIL Therapeutics, Xencor; Contracted Research: AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck and Company; Board Member (non-executive/independent): Immunocore Holdings Limited, Junshi Pharmaceuticals. RWH—Stock: Black Diamond, Xilio. JL—Consulting Fees: Iovance, Boston Biomedical, Pfizer, BMS, GSK, Novartis, Incyte, Immunocore, YKT Global, iOnctura, Apple Tree, Roche, Pierre Fabre, AstraZeneca, EUSA Pharma, MSD, Ervaxx, Merck, Ipsen, Aptitude, Eisai, Calithera, Ultmovacs, Seagen; Contracted Research: BMS, MSD, Novartis, Pfizer, Achilles, Roche, Nektar, Covance, Immunocore, Pharmacyclics, Aveo. KAM—Consulting Fees: Iovance DMC, ImaginAb SAB, Checkmate Pharma DSMB, Xilio advisor, Werewolf advisor, all except ImaginAb less than 10k/year;Temporary higher consulting fees: ImaginAb (to provide one time extra consulting up to 25k). LM—Consulting Fees: Tethis spa; Fees for Non-CE Services: Roche. SSR—Consulting Fees: Amgen, BMS, Genentech/Roch, Merck, AstraZeneca, Takeda, Eisai, Daiichi Sankyo, Sanofi, GSK, Lilly; Contracted Research: Tesaro, Merck, AstraZeneca, Advaxis, BMS, Amgen, Takeda, Genmab, GSK. MMR—Consulting Fees: BMS, Tolmar, WebMD; Contracted Research: Novartis, Pfizer, Ipsen, TerSera, Merck, Pierre Fabre, Roche, AstraZeneca, BMS, Bayer, DebioPharm. BIR—Consulting Fees: BMS, Pfizer, GNE/Roche, Aveo, Synthorx, Compugen, Merck, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, GSK, Shionogi, Eisai; Contracted Research: Pfizer, F. Hoffmann-La Roche, Incyte, AstraZeneca, Taris, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, Bristol Myers Squibb, Mirati Therapeutics, Merck, Surface Oncology, Dragonfly Therapeutics, Aravive, Exelixis; Ownership Interest (less than 5%): PTC therapeutics. MS—Consulting Fees: Adaptimmune, Pfizer, Kadmon, Pierre-Fabre, Biond, Nextcure, Incyte, Alligator, Bristol Myers, Ocellaris, Simcha, Rootpath, Numab, Evolveimmune, Biontech, Immunocore, Glaxo Smith Kline, Adagene, Asher, Kanaph, iTEOS, Genocea, Trillium, Sapience, Targovax, Molecular Partners, Ontario Institute for Cancer Research, Jazz Pharmaceuticals, Gilead, Innate pharma, Tessa, Stcube, Oncosec, Regeneron, AstraZeneca, Agenus, Idera, Apexigen, Verastem, Rubius, Genentech-Roche, Boston Pharmaceutical, Servier, Dragonfly, Boehringer Ingelheim, Nektar, Pieris, AbbVie, Zelluna, Seattle Genetics; Stock options: Adaptive Biotechnologies, Amphivena, Intensity, Actym, Evolveimmune, Nextcure, Repertoire, Oncohost, Rootpath, Asher; Stock: Johnson and Johnson, Glaxo-Smith Kline. SITC staff: SMW—Shares owned: Pacific Biosciences, Editas Medicine. ME, AK—Nothing to disclose., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Quantitative systems pharmacology (QSP) modeling is an emerging mechanistic computational approach that couples drug pharmacokinetics/pharmacodynamics and the course of disease progression. It has begun to play important roles in drug development for complex diseases such as cancer, including triple-negative breast cancer (TNBC). The combination of the anti-PD-L1 antibody atezolizumab and nab-paclitaxel has shown clinical activity in advanced TNBC with PD-L1-positive tumor-infiltrating immune cells. As tumor-associated macrophages (TAMs) serve as major contributors to the immuno-suppressive tumor microenvironment, we incorporated the dynamics of TAMs into our previously published QSP model to investigate their impact on cancer treatment. We show that through proper calibration, the model captures the macrophage heterogeneity in the tumor microenvironment while maintaining its predictive power of the trial results at the population level. Despite its high mechanistic complexity, the modularized QSP platform can be readily reproduced, expanded for new species of interest, and applied in clinical trial simulation., Competing Interests: Dr. Emens has had research funding from Genentech, F Hoffman La Roche, EMD Serono, Merck, AstraZeneca, Tempest, Bolt, Silverback, Takeda, CytomX, Compugen, Abbvie, BMS, Next Cure, Immune Onc. She has served as a paid consultant for, F Hoffman La Roche, Genentech, Macrogenics, Lilly, Chug, Silverback, Shionogi, CytomX, GPCR, Immunitas, DNAMx, Gilead, and Mersana. Dr. Emens also has an executive role at the Society for Immunotherapy of Cancer and has ownership interest in Molecuvax. Dr. Popel is a consultant to AsclepiX Therapeutics and CytomX Therapeutics. He receives research funding from AstraZeneca, Boehringer Ingelheim, CytomX Therapeutics. Dr Cesar Santa-Maria has research funding from Pfizer, AstraZeneca, Novartis, Bristol Meyers Squibb and has served on advisory boards for Bristol Meyers Squibb, Genomic Health, Seattle Genetics, Athenex, Halozyme and Polyphor. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict-of-interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Dr. Santa-Maria has research funding from Pfizer, Astrazeneca, Novartis, Bristol Meyers Squibb and has served on advisory boards for Bristol Meyers Squibb, Genomic Health, Seattle Genetics, Athenex, Halozyme and Polyphor., (© 2022 The Author(s).)

Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor clinical outcomes. Chemoimmunotherapy improves outcomes in high-risk, early-stage disease, but not all patients benefit. Baldominos and colleagues 1 drill down into early TNBC sub-microenvironments using single-cell technologies, characterizing quiescent cancer cell niches that may drive immunotherapy resistance and disease relapse., Competing Interests: Declaration of interests LAE has participated on advisory boards and/or received consulting fees from Genentech, F Hoffman La Roche, Chugai, GPCR, Gilead, Immutep, Immune Onc, Mersana, and Shionogi; she has received royalties from Aduro Biotech. LAE has participated on the steering committee for IMpassion130, KATE2, and KATE3. She is the current Vice President of the Society for the Immunotherapy of Cancer. ACM has received consulting fees from Bristol-Myers Squibb and Roche., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Over the past decade, immunotherapy has become an increasingly fundamental modality in the treatment of cancer. The positive impact of immune checkpoint inhibition, especially anti-programmed death (PD)-1/PD-ligand (L)1 blockade, in patients with different cancers has focused attention on the potential for other immunotherapeutic approaches. These include inhibitors of additional immune checkpoints, adoptive cell transfer (ACT), and therapeutic vaccines. Patients with advanced cancers who previously had limited treatment options available may now benefit from immunotherapies that can offer durable responses and improved survival outcomes. However, despite this, a significant proportion of patients fail to respond to immunotherapy, especially those with less immunoresponsive cancer types, and there remains a need for new treatment strategies.The virtual Immunotherapy Bridge (December 1st-2nd, 2021), organized by the Fondazione Melanoma Onlus, Naples, Italy in collaboration with the Society for Immunotherapy of Cancer addressed several areas of current research in immunotherapy, including lessons learned from cell therapies, drivers of immune response, and trends in immunotherapy across different cancers, and these are summarised here., (© 2022. The Author(s).)

Introduction: Triple negative breast cancer, defined by a lack of estrogen receptor, progesterone receptor, or human epidermal growth factor2, accounts for approximately 15% of breast cancer patients. Treatment options have historically been limited to chemotherapy, which has significant toxicity and a suboptimal impact on the five-year relapse rate and survival., Areas Covered: Transcriptomic analyses reveal that TNBC is biologically heterogenous. Predictive biomarkers based on the distinct biology of the different subtypes of TNBC should identify patients that will derive the greatest benefit from a specifically targeted therapeutic agent. Two biomarker-driven treatments have recently been approved: poly-ADP ribose polymerase inhibitors for patients with germline BRCA mutations and atezolizumab in combination with nab -paclitaxel for patients expressing PD-L1 on tumor-infiltrating immune cells., Expert Opinion: Identifying informative predictive biomarkers is critical for the optimal development of targeted drugs for TNBC. Some targeted agents, such as the antibody-drug conjugate sacituzumab govitecan-hziy and the precision medicines capivasertib and ipatisertib, have already shown promising results in early clinical trials, and the results of definitive phase 3 trials are eagerly awaited. Additionally, testing novel immunotherapies and other targeted agents in earlier stages of disease, particularly the neoadjuvant setting, is a high priority.

Triple-negative breast cancers (TNBCs) often have a high Ki-67 proliferation index and respond favorably to neoadjuvant chemotherapy (NACT) with pathologic complete response (pCR) resulting in ~40% of cases. Nevertheless, morbidity/mortality remain high, mostly due to recurrence in patients with residual disease. In contrast, the incidence and clinical features of TNBC with low proliferation (TNLP), defined as TNBC with a Ki-67 index of ≤30% remains unknown. We report 70 cases of TNLP identified at our center from 2008 to 2018, including 18 treated with NACT. TNLP tumors represent <1% of all breast cancers, and ~5-10% of TNBCs. Ninety percent of carcinomas were grade I/II and 70% were either pure apocrine or showed apocrine differentiation. Fifty cases had available immunohistochemistry results; 80%, 84%, 22%, and 20% were positive for AR, INPP4B, nestin, and SOX10, respectively. With a median follow-up of 72 months, 14% experienced recurrence, and 11% died of breast cancer. The tumor stage was prognostic. Among 39 stage-I patients, 18 (46%) received chemotherapy, but this did not impact survival. There was a trend for improved recurrence-free survival with chemotherapy in stage-II patients. Of the 18 patients treated with NACT, 2 (11%) showed pCR; these were notable for either high stromal TILs or a high mitotic count despite a low Ki-67 index. TNLPs are enriched in low to intermediate-grade carcinomas with apocrine features. Due to overall good prognosis of stage-I TNLP and the lack of clear benefit of chemotherapy, de-escalation of chemotherapy may be considered in select patients with stage-I TNLP., (© 2022. The Author(s).)

Predictive biomarker testing on metastatic breast cancer is essential for determining patient eligibility for targeted therapeutics. The National Comprehensive Cancer Network currently recommends assessment of specific biomarkers on metastatic tumor subtypes, including hormone receptors, HER2, and BRCA1/2 mutations, on all newly metastatic breast cancers subtypes; programmed death-ligand 1 on metastatic triple-negative carcinomas; and PIK3CA mutation status on estrogen receptor-positive carcinomas. In select circumstances mismatch repair protein deficiency and/or microsatellite insufficiency, tumor mutation burden, and NTRK translocation status are also testing options. Novel biomarker testing, such as detecting PIK3CA mutations in circulating tumor DNA, is expanding in this rapidly evolving arena., Competing Interests: Disclosure G. Jagannathan: None; M.J. White: None; R.R. Xian: None; L.A. Emens: honoraria from AbbVie, Amgen, Celgene, Chugai, GCPR, Gilead, Gritstone, MedImmune, Peregrine, Shionogi, and Syndax; honoraria and travel support from AstraZeneca, Bayer, MacroGenics, Replimune, and Vaccinex; travel support from Bristol Myers Squibb, Genentech/Roche, and Novartis; potential future stock from Molecuvax; institutional support from AbbVie, Aduro Biotech, AstraZeneca, the Breast Cancer Research Foundation, Bristol Myers Squibb, Bolt Therapeutics, Compugen, Corvus, CyTomX, the US Department of Defense, EMD Serono, Genentech, Maxcyte, Merck, the National Cancer Institute, the NSABP Foundation, SU2C, Silverback, Roche, the Translational Breast Cancer Research Consortium, Takeda, Tempest, and HeritX; royalties from Aduro Biotech; A. Cimino-Mathews: Research grants to institution from Bristol-Myers Squibb; consultancy/honoraria to self from Bristol-Myers Squibb and Roche., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Breast cancer has historically been considered a non-immunogenic tumor. Multiple studies over the last 10-15 years have demonstrated that a small subset of breast cancers is immune-activated, with PD-L1 expression and/or TILs in the tumor microenvironment. The PD-1 inhibitor pembrolizumab in combination with chemotherapy is now approved by the US FDA for the first-line treatment of metastatic PD-L1 + triple negative breast cancer, and the PD-L1 inhibitor atezolizumab has also demonstrated clinical activity. The median progression-free survival for pembrolizumab or atezolizumab combined with chemotherapy increased with the addition of immunotherapy by 4.1 months and 2.5 months, respectively. Despite this success, there is major room for improvement. Clinical benefit is modest. Only about 40% of triple negative breast cancers are PD-L1 + , not all PD-L1 + patients with advanced triple negative breast cancer respond, and immunotherapy is not yet approved for advanced PD-L1-negative triple negative breast cancer, HER2 + breast cancer, or ER + breast cancer. It is likely that redundant pathways of immune suppression are active in breast cancer, or that important pathways of immune activation are silent. In this review, we discuss emerging strategies for targeting multiple pathways of immunoregulation in advanced breast cancer with dual immune checkpoint inhibition, bispecific antibodies, and novel antibody drug conjugates. We also discuss the potential of nanotechnology to improve the delivery of immunotherapeutics to the breast tumor microenvironment to enhance their antitumor activity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Despite advances, there continues to be unmet need in breast cancer. Combining anti-programmed death-ligand 1 (PD-L1) cancer immunotherapy atezolizumab with other targeted therapies may enhance T-cell-dependent cytolytic antitumor activity., Methods: This open-label, phase Ib study evaluated the safety of atezolizumab-based combinations with antibody-dependent cellular cytotoxicity or antibody-drug conjugate (ADC) agents. Patients with unresectable human epidermal growth factor receptor 2-positive (HER2 + ) locally advanced or metastatic breast cancer (mBC) received atezolizumab with trastuzumab/pertuzumab, atezolizumab with the ADC ado-trastuzumab emtansine (T-DM1), or atezolizumab with trastuzumab/pertuzumab and docetaxel. In an early-breast cancer (eBC) "window of opportunity" study, patients with operable HER2 + locally advanced or inflammatory eBC received neoadjuvant atezolizumab with trastuzumab/pertuzumab or atezolizumab/T-DM1, followed by docetaxel, carboplatin, and trastuzumab/pertuzumab. Exploratory outcomes included tumor response and biomarkers., Results: By March 15, 2019, 73 patients were enrolled. Safety findings were consistent with the treatment components' individual profiles. Objective responses were observed in 2 of 6 and 5 of 14 patients in 2 mBC cohorts receiving atezolizumab/T-DM1 and in 6 of 6 patients with mBC receiving atezolizumab, trastuzumab/pertuzumab, and docetaxel. PD-L1 in immune cells was the only biomarker that increased with atezolizumab/T-DM1. In the window of opportunity cohorts, PD-L1 levels and CD8 + T-cell infiltration increased from baseline in HER2 + eBC tumors receiving atezolizumab with trastuzumab/pertuzumab or T-DM1, irrespective of response. Despite increases in T-cell and B-cell gene signatures with trastuzumab/pertuzumab, but not T-DM1, neither combination promoted T-cell receptor clonal expansion., Conclusion: Atezolizumab with antibody-dependent cellular cytotoxicity or ADC agents appears safe and may activate the adaptive immune system of patients with HER2 + eBC tumors more than those with mBC tumors., Competing Interests: Disclosure All authors have received grants and nonfinancial support from F. Hoffmann-La Roche during the conduct of the study. E.P.H. reports research funding to her institution from AbbVie, Acerta Pharma, Amgen, Aravive, ArQule, Arvinas, AstraZeneca, Black Diamond Therapeutics, Boehringer Ingelheim, Clovis Oncology, Compugen, Curis, CytomX, Daiichi Sankyo, Dana-Farber Cancer Hospital, Deciphera Pharmaceuticals, eFFECTOR Therapeutics, EMD Serono, Fochon Pharmaceuticals, Fujifilm, G1 Therapeutics, Genentech/Roche, H3 Biomedicine, Harpoon Therapeutics, Hutchison MediPharma, ImmunoGen, Immunomedics, Infinity Pharmaceuticals, InventisBio, Karyopharm, Leap Therapeutics, Lilly, Lycera, MacroGenics, MedImmune, Medivation, Merck, Mersana Therapeutics, Merus, Millennium Pharmaceuticals, Molecular Templates, Novartis, NuCana, Olema Oncology, OncoMed Pharmaceuticals, Onconova Therapeutics, Oncothyreon, Fosun Orinove PharmaTech, Pfizer, PharmaMar, Plexxikon, Polyphor, Puma Biotechnology, Radius Health, Regeneron Pharmaceuticals, Rgenix, Seattle Genetics, Sermonix Pharmaceuticals, Silverback Therapeutics, Stemcentrx, Sutro Biopharma, Syndax, Syros Pharmaceuticals, Taiho, Takeda, TapImmune, Tesaro, Torque Pharma, Verastem Oncology, Zenith Epigenetics, and Zymeworks; has acted in an advisory or consultancy role with fees paid to her institution from AstraZeneca, Black Diamond Therapeutics, Boehringer Ingelheim, CytomX, Daiichi Sankyo, Dantari, Genentech/Roche, H3 Biomedicine, Lilly, Merck, Mersana Therapeutics, Novartis, Pfizer, Puma Biotechnology, and Silverback Therapeutics; and has received travel support from AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, and Puma Biotechnology. V.K. reports research funding from Eisai; has acted in an advisory or consultancy role for Amgen, AstraZeneca, Athenex Oncology, Celldex Therapeutics, Daiichi Sankyo, Eisai, Puma Biotechnology, and Seattle Genomics; and has served on speakers bureaus for Celgene, Eisai, Genentech, Genomic Health, Novartis, Pfizer, and Puma Biotechnology. C.F. has acted in an advisory or consultancy role for Cardinal Health, EMD Serono, Lilly, Novartis, Pfizer, Genentech/Roche, and Seattle Genetics/Astellas. G.A.V. reports research funding from AstraZeneca, Bristol Myers Squibb, Celcuity, GTx Inc, Halozyme, Immunomedics, Lilly, Merck, Pfizer, Puma Biotechnology, Genentech/Roche, and Tesaro; has acted in an advisory or consultancy role for Immunomedics, Lilly, Pfizer, Puma Biotechnology, and Genentech/Roche; and has served on speakers bureaus for AstraZeneca, Lilly, Novartis, Pfizer, and Puma Biotechnology. P.J.W. has acted in an advisory or consultancy role with fees paid to her institution from Genentech/Roche. M.P. is an employee of and reports stock ownership in Roche. S.Y.C. is an employee of Genentech/Roche and reports stock ownership in Roche. J.R. is an employee of Genentech and reports stock ownership in Roche. K.G. is a contracted biostatistician for Genentech/Roche. L.M. is an employee of Genentech/Roche and reports stock ownership in Roche. Y.L. is an employee of Genentech/Roche and reports stock ownership in Roche. L.A.E. reports research funding from Aduro Biotech, AstraZeneca, Bristol Myers Squibb, Bolt Biotherapeutics, Breast Cancer Research Foundation, Corvus Pharmaceuticals, US Department of Defense, EMD Serono, Genentech, HeritX, MacroGenics, MaxCyte, Merck, NSABP Foundation, National Cancer Institute, Novartis, Roche, Silverback Therapeutics, and Tempest Therapeutics; has acted in an advisory or consultancy role for AbbVie, Amgen, AstraZeneca, Bayer, Celgene, Chugai, CytomX, Genentech, Gritstone Oncology, Lilly, MacroGenics, MedImmune, Peregrine Pharmaceuticals, Replimune, Roche, Shionogi, Syndax, and Vaccinex; has received travel support from Bristol Myers Squibb, Genentech/Roche, and Novartis; has received nonfinancial compensation from eTheRNA; and has received royalties or milestone payments from Aduro Biotech and MolecuVax., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: This study evaluated epidemiologic and immune factors associated with pathologic complete response (pCR), breast cancer-specific survival (BCSS) and disease-free survival (DFS) outcomes in inflammatory (IBC) and locally advanced breast cancer (LABC) patients., Methods: Tumor-infiltrating lymphocytes (TILs) and CD20 + B-cell frequencies (CD20 + ), and PD-L1 expression on tumor (PD-L1 + carcinoma cells) and immune (PD-L1 + TILs) cells were analyzed by immunohistochemistry along with clinicopathologic factors as modifiers of pCR and outcomes in 221 IBC and 162 LABC patients. Analysis included Kaplan-Meier curves and Cox proportional hazard models., Results: IBC and LABC display similar levels of TILs, CD20 + , and combined CD20 + and PD-L1 + TILs (CD20 + PD-L1 + TILs), while LABC contained more PD-L1 + TILs and PD-L1 + carcinoma cells. Absence of lymphovascular involvement, high TILs, PD-L1 + carcinoma cells, and combined CD20 + and PD-L1 + carcinoma cells correlated with pCR in IBC and LABC patients. High PD-L1 + TILs correlated with pCR only in LABC; less lymph node involvement at diagnosis, CD20 + and CD20 + PD-L1 + TILs correlated with pCR only in IBC (P < 0.04, all comparisons). Achievement of pCR in IBC and LABC patients correlated with BCSS and DFS (P < 0.02). In multivariate analyses, pCR remained an independent prognostic factor of improved DFS in IBC and LABC patients, but of BCSS in only LABC. CD20 + PD-L1 + TILs remained an independent prognostic factor of improved DFS and BCSS only in IBC., Conclusion: CD20 + PD-L1 + TILs are an independent prognostic biomarker of improved outcomes in IBC, but not LABC. Selecting IBC patients by CD20 and PD-L1 status could stratify patients and potentially identify those in whom activating CD20 agents and anti-PD-1/PD-L1 therapy could be explored., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In the phase III IMpassion130 study, atezolizumab plus nab-paclitaxel (A+nP) showed clinical benefit in advanced or metastatic triple-negative breast cancer patients who were programmed death-ligand 1 (PD-L1)+ (tumor-infiltrating immune cells [IC] ≥1%) using the SP142 immunohistochemistry assay. Here we evaluate 2 other PD-L1 assays for analytical concordance with SP142 and patient-associated clinical outcomes., Methods: Samples from 614 patients (68.1% of intention-to-treat population) were centrally evaluated by immunohistochemistry for PD-L1 status on IC (VENTANA SP142, SP263, Dako 22C3) or as a combined positive score (CPS; 22C3)., Results: Using SP142, SP263, and 22C3 assays, PD-L1 IC ≥1% prevalence was 46.4% (95% confidence interval [CI] = 42.5% to 50.4%), 74.9% (95% CI = 71.5% to 78.3%), and 73.1% (95% CI = 69.6% to 76.6%), respectively; 80.9% were 22C3 CPS ≥1. At IC ≥1% (+), the analytical concordance between SP142 and SP263 and 22C3 was 69.2% and 68.7%, respectively. Almost all SP142+ cases were captured by other assays (double positive), but several SP263+ (29.6%) or 22C3+ (29.0%) cases were SP142- (single positive). A+nP clinical activity vs placebo+nP in SP263+ and 22C3+ patients (progression-free survival [PFS] hazard ratios [HRs] = 0.64 to 0.68; overall survival [OS] HRs = 0.75 to 0.79) was driven by double-positive cases (PFS HRs = 0.60 to 0.61; OS HRs = 0.71 to 0.75) rather than single-positive cases (PFS HRs = 0.68 to 0.81; OS HRs = 0.87 to 0.95). Concordance for harmonized cutoffs for SP263 (IC ≥4%) and 22C3 (CPS ≥10) to SP142 (IC ≥1%) was subpar (approximately 75%)., Conclusions: 22C3 and SP263 assays identified more patients as PD-L1+ (IC ≥1%) than SP142. No inter-assay analytical equivalency was observed. Consistent improved A+nP efficacy was captured by the SP142 PD-L1 IC ≥1% subgroup nested within 22C3 and SP263 PD-L1+ (IC ≥1%) populations., (© The Author(s) 2021. Published by Oxford University Press.)