Strategies for Increasing Pancreatic Tumor Immunogenicity

Johnson, Burles A.; Yarchoan, Mark; Lee, Valerie; Laheru, Daniel A.; Jaffee, Elizabeth M.

doi:10.1158/1078-0432.ccr-16-2318

Cited by 141 publications

(99 citation statements)

References 184 publications

(189 reference statements)

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“…PDAC patients have not benefited from single agent or combination ICI therapy (194)(195)(196) despite increased expression of PD-L1 in tumors (197)(198)(199). Significant efforts are underway to improve immunotherapy efficacy, including studies investigating regulatory B cell inhibition (e.g., Bruton's Tyrosine Kinase (BTK) inhibitors), IDO inhibition, and vaccine therapy (200). Though a predominant target in B cell malignancies, BTK in PDAC is shown to induce B cell-and macrophage-mediated T cell suppression, which BTK inhibitors (i.e., ibrutinib) restore T celldependent antitumor immunity and improve responsiveness to chemotherapy in preclinical studies (201).…”

Section: Pancreatic Cancermentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

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Section: Pancreatic Cancermentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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“…One potential strategy for priming the tumor microenvironment (TME) for immune checkpoint therapy is to induce tumor infiltrating lymphocytes and adaptive immune resistance pathways through the use of therapeutic cancer vaccines. 4 The GVAX colon vaccine is an allogeneic, whole-cell, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting cellular immunotherapy that induces T-cell immunity against a broad range of colon cancer-associated antigens. It consists of two CRC cell lines (SW837, SW620), and a bystander cell line transfected with a plasmid vector encoding human GM-CSF as a vaccine adjuvant.…”

Section: Introductionmentioning

confidence: 99%

A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer

et al. 2019

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Background Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single‐agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole‐cell, granulocyte‐macrophage colony‐stimulating factor ‐secreting cellular immunotherapy that induces T‐cell immunity against tumor‐associated antigens and has previously been studied in combination with low‐dose cyclophosphamide (Cy) to inhibit regulatory T cells. Methods We conducted a single‐arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21‐day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression‐free survival, changes in carcinoembryonic antigen (CEA) levels, and immune‐related correlates. Results Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression‐free survival was 82 days (95% confidence interval [CI], 48‐97 days) and the median overall survival was 213 days (95% CI 179‐441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment‐related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre‐ and on‐treatment biopsy specimens showed increases in programmed death‐ligand 1 expression and tumor necrosis in a subset of patients. Conclusions GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response.

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“…Because Myc and Ras serve as convergent downstream effectors for the diverse upstream driver mutations that cause cancer, targeting them offers a therapeutic strategy, potentially synergizing with the current therapeutics and ongoing clinical trials discussed in this CCR Focus section (2, 5, 45). Indeed, our own and others’ studies using switchable variants of oncogenic Myc and Ras in multiple tumor types (46–53) demonstrate that de-activation of either Myc or KRas G12D triggers rapid and profound regression in many diverse types of experimental tumors in mice, including PDAC (54–56).…”

Section: Introductionmentioning

confidence: 99%

Re-engineering the Pancreas Tumor Microenvironment: A "Regenerative Program" Hacked

Evan

Hah

Littlewood

et al. 2017

Clinical Cancer Research

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The “hallmarks” of pancreatic ductal adenocarcinoma (PDAC) include proliferative, invasive and metastatic tumor cells and an associated dense desmoplasia comprised of fibroblasts, pancreatic stellate cells, extracellular matrix and immune cells. The oncogenically-activated pancreatic epithelium and its associated stroma are obligatorily interdependent, with the resulting inflammatory and immune-suppressive microenvironment contributing greatly to the evolution and maintenance of PDAC. The peculiar pancreas-specific tumor phenotype is a consequence of oncogenes hacking the resident pancreas regenerative program, a tissue specific repair mechanism regulated by discrete super enhancer networks. Defined as genomic regions containing clusters of multiple enhancers, super enhancers play pivotal roles in cell/tissue specification, identity and maintenance. Hence, interfering with such super enhancer driven repair networks should exert a disproportionately disruptive effect on tumor versus normal pancreatic tissue. Novel drugs that directly or indirectly inhibit processes regulating epigenetic status and integrity, including those driven by histone deacetylases, histone methyltransferase and hydroxylases, DNA methyltransferases, various metabolic enzymes, and bromodomain and extra-terminal motif proteins (BETs) have shown the feasibility of disrupting super enhancer-dependent transcription in treating multiple tumor types, including PDAC. The idea that pancreatic adenocarcinomas rely on embedded super enhancer transcriptional mechanism suggests a vulnerability that can be potentially targeted as novel therapies for this intractable disease.

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Strategies for Increasing Pancreatic Tumor Immunogenicity

Cited by 141 publications

References 184 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer

Re-engineering the Pancreas Tumor Microenvironment: A "Regenerative Program" Hacked

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