Cancer immunotherapies are more effective in tumors with robust T cell infiltrates, but mechanisms to convert T cell-devoid tumors with active immunosuppression to those capable of recruiting T cells ...remain incompletely understood. Here, using genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDA), we demonstrate that a single dose of agonistic CD40 antibody with chemotherapy rendered PDA susceptible to T cell-dependent destruction and potentiated durable remissions. CD40 stimulation caused a clonal expansion of T cells in the tumor, but the addition of chemotherapy optimized myeloid activation and T cell function. Although recent data highlight the requirement for innate sensors in cancer immunity, these canonical pathways—including TLRs, inflammasome, and type I interferon/STING—played no role in mediating the efficacy of CD40 and chemotherapy. Thus, CD40 functions as a non-redundant mechanism to convert the tumor microenvironment immunologically. Our data provide a rationale for a newly initiated clinical trial of CD40 and chemotherapy in PDA.
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•CD40 stimulation converts T-cell-deficient tumors to immunologically replete sites•CD40 mediates clonal T cell expansion with decreased regulatory T cells•Functional adaptive immune responses require both CD40 stimulation and chemotherapy•Converted tumors undergo durable responses independently of innate immune sensors
Immunologically “cold” tumors lack T cells and are hyporesponsive to immunotherapies. Byrne and Vonderheide show that CD40 stimulation, with chemotherapy, converts a “cold” tumor to a site of T cell infiltration and destruction with durable responses. Functional immune responses are independent of innate immune sensors important in other settings.
The biological and functional heterogeneity between tumors—both across and within cancer types—poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and ...immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell-inflamed and non-T-cell-inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co-injecting tumor cell clones revealed the non-T-cell-inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor-cell-intrinsic production of the chemokine CXCL1 as a determinant of the non-T-cell-inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell-intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy.
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•Generated a library of congenic pancreatic cancer cell clones derived from KPC mice•Each tumor elicited unique immune infiltration correlating with therapeutic response•Tumors lacking T cells exhibit different epigenetic and transcriptomic status•CXCL1 was increased in therapy-resistant tumors that lacked T cell infiltration
Using a library of pancreatic cancer cell clones, Li et al. identify heterogeneous and multifactorial pathways regulating tumor-cell-intrinsic mechanisms that dictate the immune microenvironment and thereby responses to immunotherapy. This tumor clone library provides a tool for identifying new targets responsible for thwarting responses to immunotherapy in resistant tumors.
Pancreatic cancer is the third-leading cause of cancer mortality in the USA, recently surpassing breast cancer. A key component of pancreatic cancer's lethality is its acquired immune privilege, ...which is driven by an immunosuppressive microenvironment, poor T cell infiltration, and a low mutational burden. Although immunotherapies such as checkpoint blockade or engineered T cells have yet to demonstrate efficacy, a growing body of evidence suggests that orthogonal combinations of these and other strategies could unlock immunotherapy in pancreatic cancer. In this Review article, we discuss promising immunotherapies currently under investigation in pancreatic cancer and provide a roadmap for the development of prevention vaccines for this and other cancers.
Cancer immunotherapy has revolutionized the treatment landscape in medical oncology, but its efficacy has been variable across patients. Biomarkers to predict such differential response to ...immunotherapy include cytotoxic T lymphocyte infiltration, tumor mutational burden, and microsatellite instability. A growing number of studies also suggest that baseline tumor burden, or tumor size, predicts response to immunotherapy. In this review, we discuss the changes in immune profile and therapeutic responses that occur with increasing tumor size. We also overview therapeutic approaches to reduce tumor burden and favorably modulate the immune microenvironment of larger tumors.
Immunologically-cold tumors including glioblastoma (GBM) are refractory to checkpoint blockade therapy, largely due to extensive infiltration of immunosuppressive macrophages (Mϕs). Consistent with a ...pro-tumor role of IL-6 in alternative Mϕs polarization, we here show that targeting IL-6 by genetic ablation or pharmacological inhibition moderately improves T-cell infiltration into GBM and enhances mouse survival; however, IL-6 inhibition does not synergize PD-1 and CTLA-4 checkpoint blockade. Interestingly, anti-IL-6 therapy reduces CD40 expression in GBM-associated Mϕs. We identify a Stat3/HIF-1α-mediated axis, through which IL-6 executes an anti-tumor role to induce CD40 expression in Mϕs. Combination of IL-6 inhibition with CD40 stimulation reverses Mϕ-mediated tumor immunosuppression, sensitizes tumors to checkpoint blockade, and extends animal survival in two syngeneic GBM models, particularly inducing complete regression of GL261 tumors after checkpoint blockade. Thus, antibody cocktail-based immunotherapy that combines checkpoint blockade with dual-targeting of IL-6 and CD40 may offer exciting opportunities for GBM and other solid tumors.
Innate immune receptors such as toll-like receptors (TLRs) provide critical molecular links between innate cells and adaptive immune responses. Here, we studied the CD40 pathway as an alternative ...bridge between dendritic cells (DCs) and adaptive immunity in cancer. Using an experimental design free of chemo- or radiotherapy, we found CD40 activation with agonistic antibodies (⍺CD40) produced complete tumor regressions in a therapy-resistant pancreas cancer model, but only when combined with immune checkpoint blockade (ICB). This effect, unachievable with ICB alone, was independent of TLR, STING, or IFNAR pathways. Mechanistically, αCD40/ICB primed durable T cell responses, and efficacy required DCs and host expression of CD40. Moreover, ICB drove optimal generation of polyfunctional T cells in this “cold” tumor model, instead of rescuing T cell exhaustion. Thus, immunostimulation via αCD40 is sufficient to synergize with ICB for priming. Clinically, combination αCD40/ICB may extend efficacy in patients with “cold” and checkpoint-refractory tumors.
Melanoma-associated vitiligo is the best-studied example of the linkage between tumor immunity and autoimmunity. Although vitiligo is an independent positive prognostic factor for melanoma patients, ...the autoimmune destruction of melanocytes was long thought to be merely a side effect of robust anti-tumor immunity. However, new data reveal a key role for vitiligo in supporting T cell responses to melanoma. This research perspective reviews the history of melanoma-associated vitiligo in patients, the experimental studies that form the basis for understanding this relationship, and the unique characteristics of melanoma-specific CD8 T cells found in hosts with vitiligo. We also discuss the implications of our recent findings for the interpretation of patient responses, and the design of next-generation cancer immunotherapies.
Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice ...and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose.
This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.
Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months 21·4–22·7, cohort B2 18·2 months 17·0–18·9, cohort C1 17·9 months 14·3–19·7, cohort C2 15·9 months 12·7–16·1). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 67%; five in B1, seven in B2, four in C1, four in C2), anaemia (11 37%; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine 30%; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six 20% of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2).
APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population.
Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.
Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a ...randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.
Resistance to immunotherapy is one of the biggest problems of current oncotherapeutics. While T cell abundance is essential for tumor responsiveness to immunotherapy, factors that define the T ...cell-inflamed tumor microenvironment are not fully understood. We used an unbiased approach to identify tumor-intrinsic mechanisms shaping the immune tumor microenvironment (TME), focusing on pancreatic adenocarcinoma because it is refractory to immunotherapy and excludes T cells from the TME. From human tumors, we identified ephrin-A receptor 2 (EPHA2) as a candidate tumor-intrinsic driver of immunosuppression. Epha2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy. We found that prostaglandin endoperoxide synthase 2 (PTGS2), the gene encoding cyclooxygenase- 2, lies downstream of EPHA2 signaling through TGF-beta and is associated with poor patient survival. Ptgs2 deletion reversed T cell exclusion and sensitized tumors to immunotherapy; pharmacological inhibition of PTGS2 was similarly effective. Thus, EPHA2/PTGS2 signaling in tumor cells regulates tumor immune phenotypes; blockade may represent a therapeutic avenue for immunotherapy-refractory cancers. Our findings warrant clinical trials testing the effectiveness of therapies combining EPHA2/TGF-beta/PTGS2 pathway inhibitors with antitumor immunotherapy and may change the treatment of notoriously therapy-resistant pancreatic adenocarcinoma.
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