A first-in-human phase 1 study of a novel PARP7 inhibitor RBN-2397 in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3000-3000
Author(s):  
Gerald Steven Falchook ◽  
Manish R. Patel ◽  
Timothy A. Yap ◽  
Kristen McEachern ◽  
Kristy Kuplast-Barr ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cells ◽  
Nucleic Acid ◽  
Solid Tumors ◽  
Cd8 T Cells ◽  
Type I ◽  
Advanced Solid Tumors ◽  
Type I Ifn ◽  
Intermittent Schedule

3000 Background: Targeting cytosolic nucleic acid sensing pathways and the Type I interferon (IFN) response is an emerging therapeutic strategy in oncology. PARP7 is a member of the monoPARP class of enzymes and a newly identified negative regulator of nucleic acid sensing in tumor cells. PARP7 expression is increased by cellular stress and aromatic hydrocarbons, and the PARP7 gene is amplified in multiple cancers. RBN-2397 is a potent, selective inhibitor of PARP7. In preclinical models, RBN-2397 restored Type I IFN signaling in tumors, caused complete tumor regressions, and induced adaptive immunity. Methods: Patients (pts) with advanced solid tumors were treated with RBN-2397 on either a continuous or 14-of-21-day intermittent schedule using a 3+3 dose escalation design. Primary objective: establish MTD and/or RP2D. Secondary obj.: safety, activity, PK of unmicronized/micronized tablets. Exploratory obj.: Pd. Results: As of 4 January 2021, 47 pts were treated: 25 pts in the intermittent schedule (25 to 500 mg BID) and 22 patients in the continuous schedule (100 to 400 mg BID). The most frequent RBN-2397-related AEs (all grades) were dysgeusia (26%), decreased appetite (13%), fatigue (11%), and diarrhea (11%). Gr 3/4 RBN-2397-related AEs all occurred in 7 pts (15%) at doses ≥ 200 mg: diarrhea (2 pts, 4%), increased ALT, AST, and bilirubin (1 pt, 2%), and fatigue, anemia, neutropenia, and thrombocytopenia in 1 pt (2%) each. The 2 DLTs were Gr 3 febrile neutropenia (400 mg continuous schedule) and Gr 4 increase in ALT/AST (500 mg intermittent schedule). Plasma exposures generally increased dose dependently with the majority at or above the projected efficacious range based on animal studies. All evaluable baseline tumor biopsies showed evidence of PARP7 expression as measured by mRNA in situ hybridization (n = 11; Median tumor H score: 128). In 5 evaluable tumor biopsy pairs, increases in interferon-stimulated gene expression were observed post RBN-2397, consistent with activation of Type I IFN. CXCL10 mRNA increased in all evaluable on-treatment biopsies (1.5 to 8-fold). Several on-treatment biopsies showed enrichment for immune response gene sets that was accompanied by an increase in CD8+ T cells and Granzyme B expression, evidence for induction of an adaptive immune response post RBN-2397. This increase in immune response related genes and CD8+ T cells was observed in a pt with metastatic squamous NSCLC who has been on study for 16+ months. 1 pt with HR+, HER2- breast cancer achieved a confirmed PR at 100 mg and 8 pts had SD for ≥18 weeks (RECIST 1.1). Conclusions: To date, RBN-2397 is well tolerated and demonstrates dose dependent increases in plasma exposures, evidence of target inhibition, and preliminary signs of clinical activity. Determination of MTD/RP2D is imminent and study expansion is planned to evaluate safety and efficacy in squamous NSCLC, HNSCC, HR+ breast cancer, and PARP7 amplified tumors. Clinical trial information: NCT04053673.

scholarly journals STING: a master regulator in the cancer-immunity cycle

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yuanyuan Zhu ◽  
Xiang An ◽  
Xiao Zhang ◽  
Yu Qiao ◽  
Tongsen Zheng ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Negative Effects ◽  
Independent Manner ◽  
Adaptive Immune ◽  
Cancer Immunity

Abstract The aberrant appearance of DNA in the cytoplasm triggers the activation of cGAS-cGAMP-STING signaling and induces the production of type I interferons, which play critical roles in activating both innate and adaptive immune responses. Recently, numerous studies have shown that the activation of STING and the stimulation of type I IFN production are critical for the anticancer immune response. However, emerging evidence suggests that STING also regulates anticancer immunity in a type I IFN-independent manner. For instance, STING has been shown to induce cell death and facilitate the release of cancer cell antigens. Moreover, STING activation has been demonstrated to enhance cancer antigen presentation, contribute to the priming and activation of T cells, facilitate the trafficking and infiltration of T cells into tumors and promote the recognition and killing of cancer cells by T cells. In this review, we focus on STING and the cancer immune response, with particular attention to the roles of STING activation in the cancer-immunity cycle. Additionally, the negative effects of STING activation on the cancer immune response and non-immune roles of STING in cancer have also been discussed.

scholarly journals A Lymphotoxin/Type I IFN Axis Programs CD8+T Cells To Infiltrate a Self-Tissue and Propagate Immunopathology

2015 ◽  
Vol 195 (10) ◽  
pp. 4650-4659 ◽  
Author(s):  
Dennis Ng ◽  
Blandine Maître ◽  
Derek Cummings ◽  
Albert Lin ◽  
Lesley A. Ward ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Type I ◽  
Type I Ifn

scholarly journals Influenza A Infection Enhances Cross-Priming of CD8+T Cells to Cell-Associated Antigens in a TLR7- and Type I IFN-Dependent Fashion

2010 ◽  
Vol 185 (10) ◽  
pp. 6013-6022 ◽  
Author(s):  
Joe Wei ◽  
Jason Waithman ◽  
Roleen Lata ◽  
Nicole A. Mifsud ◽  
Jonathan Cebon ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Influenza A ◽  
Type I ◽  
Type I Ifn

Vaccine for prevention of breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2580-2580
Author(s):  
A. Deisseroth ◽  
Y. Tang ◽  
J. Maynard ◽  
H. Akbulut
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cells ◽  
Adjuvant Therapy ◽  
Cd8 T Cells ◽  
In Vitro Assays ◽  
Breast Cancer Patients ◽  
Protein Boost ◽  
Her 2 ◽  
Old Mice

2580 Background: Women with high risk breast cancer still succumb to their disease despite existing programs of adjuvant therapy. Thus, new approaches for adjuvant therapy are needed. Her-2-Neu overexpression on a breast cancer cells correlates with recurrence, metastasis and resistance to chemotherapy and radiation therapy. The immune response is tolerant of tumor associated antigens (TAA) like Her-2-Neu since they have been present on epithelial cells since birth. The immune response to vaccines in women with breast cancer is limited by the diminished number of CD4 and CD8 T cells and qualitative defects of CD4 cells in individuals above the age of 50. Methods: The following strains of mice were vaccinated: 6–8 week old hMUC-1.Tg mice, and rH2N.Tg mice, as well as 18 month and 2 month old C57BL/6J mice, by injecting subcutaneously the Ad-sig-TAA/ecdCD40L vector prime followed by sc injections of the TAA/ecdCD40L protein boost. Results: Vaccination of 18 month old mice with the Ad-sig-TAA/ecdCD40L vector prime protein boost produce regressions of TAA positive sc tumor and a 5 fold increase in antigen specific spleen cells, a 10X increase in subcutaneous tumor nodules of antigen specific effector CD8 T cells by tetramers, and a 2X decrease of CD4+CD25+FOXP3+ cells. Vaccination of rH2N.Tg mice starting at 6 weeks with the Ad-sig-rH2N/ecdCD40L vector prime/protein boost prevented the development of breast cancer in 50% of the mice. The Ad-sig-hMUC-1/ecdCD40L vector prime/ hMUC-1/ecdCD40L protein boost induced hMUC-1 specific antibodies in hMUC-1.Tg mice which bound to human breast cancer specimens. The rH2N/ecdCD40L vector prime/protein boost vaccine suppressed growth of rH2N positive tumor cells and this effect was potentiated by concomitant administration of chemotherapy. Conclusions: These results suggest that the Ad-sig-TAA/ecdCD40L platform can be used to suppress the growth of existing breast cancer even in old mice and prevent the development of breast cancer. We are preparing a phase I clinical trial of this approach in the setting of breast cancer patients who have failed first line adjuvant therapy. In this trial, the vaccine will be added to established salvage therapy and both in vivo evaluations of tumor response, in vitro assays of immune response and toxicity will be measured. No significant financial relationships to disclose.

Anti-tumor immunity in mismatch repair-deficient colorectal cancers requires type I IFN–driven CCL5 and CXCL10

2021 ◽  
Vol 218 (9) ◽  
Author(s):  
Courtney Mowat ◽  
Shayla R. Mosley ◽  
Afshin Namdar ◽  
Daniel Schiller ◽  
Kristi Baker
Keyword(s):  
T Cells ◽  
Mismatch Repair ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Colorectal Cancers ◽  
Type I ◽  
Type I Ifn ◽  
Dna Mismatch ◽  
Infiltrating Lymphocytes

Colorectal cancers (CRCs) deficient in DNA mismatch repair (dMMR) contain abundant CD8+ tumor-infiltrating lymphocytes (TILs) responding to the abundant neoantigens from their unstable genomes. Priming of such tumor-targeted TILs first requires recruitment of CD8+ T cells into the tumors, implying that this is an essential prerequisite of successful dMMR anti-tumor immunity. We have discovered that selective recruitment and activation of systemic CD8+ T cells into dMMR CRCs strictly depend on overexpression of CCL5 and CXCL10 due to endogenous activation of cGAS/STING and type I IFN signaling by damaged DNA. TIL infiltration into orthotopic dMMR CRCs is neoantigen-independent and followed by induction of a resident memory-like phenotype key to the anti-tumor response. CCL5 and CXCL10 could be up-regulated by common chemotherapies in all CRCs, indicating that facilitating CD8+ T cell recruitment underlies their efficacy. Induction of CCL5 and CXCL10 thus represents a tractable therapeutic strategy to induce TIL recruitment into CRCs, where local priming can be maximized even in neoantigen-poor CRCs.

scholarly journals LTβR signaling in dendritic cells induces a type I IFN response that is required for optimal clonal expansion of CD8+T cells

2011 ◽  
Vol 108 (5) ◽  
pp. 2046-2051 ◽  
Author(s):  
Leslie Summers deLuca ◽  
Dennis Ng ◽  
Yunfei Gao ◽  
Michael E. Wortzman ◽  
Tania H. Watts ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Cd8 T Cells ◽  
Clonal Expansion ◽  
Type I ◽  
Type I Ifn

scholarly journals Dormant Tumor Cell Vaccination: A Mathematical Model of Immunological Dormancy in Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 245
Author(s):  
Reza Mehdizadeh ◽  
Seyed Peyman Shariatpanahi ◽  
Bahram Goliaei ◽  
Sanam Peyvandi ◽  
Curzio Rüegg
Keyword(s):  
Breast Cancer ◽  
Mathematical Model ◽  
Immune Response ◽  
Growth Rate ◽  
T Lymphocyte ◽  
Triple Negative ◽  
Cytotoxic T Lymphocyte ◽  
Type I ◽  
Type I Ifn ◽  
Cancer Dormancy

Triple-negative breast cancer (TNBC) is a molecular subtype of breast malignancy with a poor clinical prognosis. There is growing evidence that some chemotherapeutic agents induce an adaptive anti-tumor immune response. This reaction has been proposed to maintain the equilibrium phase of the immunoediting process and to control tumor growth by immunological cancer dormancy. We recently reported a model of immunological breast cancer dormancy based on the murine 4T1 TNBC model. Treatment of 4T1 cells in vitro with high-dose chemotherapy activated the type I interferon (type I IFN) signaling pathway, causing a switch from immunosuppressive to cytotoxic T lymphocyte-dependent immune response in vivo, resulting in sustained dormancy. Here, we developed a deterministic mathematical model based on the assumption that two cell subpopulations exist within the treated tumor: one population with high type I IFN signaling and immunogenicity and lower growth rate; the other population with low type I IFN signaling and immunogenicity and higher growth rate. The model reproduced cancer dormancy, elimination, and immune-escape in agreement with our previously reported experimental data. It predicted that the injection of dormant tumor cells with active type I IFN signaling results in complete growth control of the aggressive parental cancer cells injected at a later time point, but also of an already established aggressive tumor. Taken together, our results indicate that a dormant cell population can suppress the growth of an aggressive counterpart by eliciting a cytotoxic T lymphocyte-dependent immune response.

scholarly journals IL-12 and type I interferon prolong the division of activated CD8 T cells by maintaining high-affinity IL-2 signaling in vivo

2013 ◽  
Vol 211 (1) ◽  
pp. 105-120 ◽  
Author(s):  
Gabriel R. Starbeck-Miller ◽  
Hai-Hui Xue ◽  
John T. Harty
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Type I ◽  
Type I Ifn ◽  
Cellular Division ◽  
High Affinity ◽  
Cell Accumulation

TCR ligation and co-stimulation induce cellular division; however, optimal accumulation of effector CD8 T cells requires direct inflammatory signaling by signal 3 cytokines, such as IL-12 or type I IFNs. Although in vitro studies suggest that IL-12/type I IFN may enhance T cell survival or early proliferation, the mechanisms underlying optimal accumulation of CD8 T cells in vivo are unknown. In particular, it is unclear if disparate signal 3 cytokines optimize effector CD8 T cell accumulation by the same mechanism and how these inflammatory cytokines, which are transiently produced early after infection, affect T cell accumulation many days later at the peak of the immune response. Here, we show that transient exposure of CD8 T cells to IL-12 or type I IFN does not promote survival or confer an early proliferative advantage in vivo, but rather sustains surface expression of CD25, the high-affinity IL-2 receptor. This prolongs division of CD8 T cells in response to basal IL-2, through activation of the PI3K pathway and expression of FoxM1, a positive regulator of cell cycle progression genes. Thus, signal 3 cytokines use a common pathway to optimize effector CD8 T cell accumulation through a temporally orchestrated sequence of cytokine signals that sustain division rather than survival.

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