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Pancreatic cancer is feeling the heat
  1. Saumya Y Maru1,2,3,4 and
  2. Elizabeth M Jaffee1,2,3,4
  1. 1 Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  2. 2 Convergence Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3 Bloomberg Kimmel Immunology Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  4. 4 The Skip Viragh Center for Clinical and Translational Research, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  1. Correspondence to Dr Elizabeth M Jaffee; ejaffee{at}jhmi.edu

Abstract

Pancreatic adenocarcinoma (PDAC) is considered an immunologically ‘cold’ tumor that fails to attract or support effector T cells. Most PDACs are resistant to immune checkpoint blockade due to the complex signaling pathways that exist within its tumor microenvironment. Recent advances in genomic and proteomic technology advances are finally uncovering the complex inflammatory cellular and intercellular signals that require modulation and reprogramming. The goal is to ‘turn up the heat’ on PDACs with combination immunotherapies that incorporate T cell activating agents and immune modulatory agents, and successfully eradicate tumors. Here, we discuss progress and promising new research that is moving the field toward this goal.

  • gastrointestinal cancer
  • immunotherapy
  • combination therapy
  • tumor microenvironment - TME
  • adenocarcinoma
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An immunotherapy win against pancreatic adenocarcinoma

Programmed cell death protein 1 (PD-1) blocking antibodies are now in the National Comprehensive Cancer Network guidelines to treat the 2%–3% of patients with pancreatic adenocarcinoma (PDAC) who have microsatellite instability-high tumors. This biomarker indicates mutations in or methylation silencing of certain DNA mismatch repair genes, leading to high rates of expressed mutations that prime T cell responses within the tumor microenvironment (TME). Both pembrolizumab and nivolumab are Food and Drug Administration approved for this genetically defined syndrome, although single agent anti-PD-1 therapy is insufficient in PDAC and subgroup analyses have revealed modest outcomes for PDAC compared with other cancer types. This small group of patients with PDAC are the only ones to benefit from approved checkpoint inhibitor therapies. However, combination immunotherapy approaches are being tested in patients and are showing promise in early clinical trials.

PDAC challenges

Immune checkpoint modulators depend on available primed T cells that exhibit improved cytolytic responses when disinhibited by blockade of signaling pathways such as the PD-1/programmed death-ligand 1 (PD-L1) axis, cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and others. Engineering T cells that are isolated and genetically modified to become active ex vivo before infusing back into patients solves the problem of a lack of effector T cells but require a permissive TME to enter and unleash their tumor killing function. Unfortunately, PDACs rarely possess T cells that can be primed within the TME, and single and combination immune checkpoint agents have failed to adequately activate existing T cells. Also, the PDAC TME is one of the most complex, featuring multiple mechanisms of immune resistance and a rapid evolution of these mechanisms following therapeutic intervention, which prevents T cell entry and/or anticancer function.1

Human PDACs usually exhibit ineffective T cells within their TME. Even early stage resectable PDACs have few functional T cells, and these are often either antigen inexperienced, rendered ignorant to antigen existence, or exhausted, suggesting they have previously been exposed to antigen. Controversy exists as to whether T cells are: (1) initially attracted to and activated by the premalignant and early malignant cells before ignorance or tolerance occurs, fitting the concept of immune editing or (2) never alerted to the developing and progressing malignancy. However, increasing data suggest that the earliest premalignant lesion, pancreatic intraepithelial neoplasia-1 (PanIN 1), which almost uniformly expresses driver mutations in the oncogene KRAS, attracts cytotoxic T cells. These T cells eventually regress as the precancer transforms into PDAC and are replaced by regulatory T cells (Tregs) and suppressive monocyte populations. PanINs of all stages have also been shown to be associated with the development of tertiary lymphoid structures (TLS) that become mature with progression to PDACs.2 3 In untreated resected PDACs these TLS are often inactive, whereas neoadjuvant immunotherapy can induce TLS that are active sites of T cell activation. We reported that a vaccine alone (GVAX, made from whole PDAC tumor cell lines genetically engineered to express granulocyte-macrophage colony-stimulating factor) or given with PD-1/PD-L1 inhibitors, are not enough to fully activate T cells.4 In a small study, we also showed that adding anti-CD137 agonism can enhance T cell activation, expansion, and pathological responses in the neo-adjuvant setting. These data suggest that both agonist and antagonist T cell signals require engagement to develop the most ‘fit’ T cells that can function in the PDAC TME.4

Immunotherapy opportunities

Successful PDAC immunotherapy will require combination immune-based approaches that incorporate agents that enhance T cell activation and reduce multiple cellular signals that downregulate T cell trafficking and function within the TME (figure 1). It remains unclear how best to activate PDAC-targeted effector T cells, but preclinical and clinical studies have shown that both CD4+ and CD8+ T cells are required for the most effective antitumor response. The most direct way to induce an optimal T cell is with antigen-targeted therapeutic vaccines. Both shared and neoantigen vaccines have been tested, and when combined with immune checkpoint modulators, they have shown evidence of immune activation. So far, whole cell vaccines such as GVAX, oncogene-targeted mutated KRAS (mKRAS) vaccines, and patient-specific neoantigen vaccines have shown the induction of T cell responses against shared antigens (ie, mesothelin), mKRAS, and one or more neoantigens, respectively, primarily in peripheral blood.5 6 Furthermore, none of these vaccination strategies have been compared head-to-head to identify the optimal approach. Non-specific T cell-inducing approaches, including chemotherapy, radiation therapy, epigenetic modulators, and DNA damage repair small molecule therapies, have also shown evidence of T cell infiltration into PDACs. Anti-CD40 agents that enhance antigen presentation and T cell priming, when administered alongside chemotherapy, have shown evidence of intratumoral CD4+ T cell infiltration, although this did not translate to an improvement in overall survival compared with historical controls.7

Figure 1

Examples of strategies to increase antitumor immune activity in PDAC. This figure is a depiction of the complexities of the PDAC TME. It is characterized by a high degree of fibrosis and a dearth of immune effector cells. Recent single cell and spatial technologies are rapidly improving our understanding of inflammatory pathways and cellular cross-talk, examples of which are shown here. Ongoing preclinical and clinical studies are focused on increasing antigen processing and presentation, improving T cell activation and function in the TME, monocyte reprogramming, and remodeling CAFs. One approach has relied on vaccines (whole cell, dendritic cell, viruses including oncolytic viruses, DNA, mRNA, and peptide/protein vaccines) ± immune modulators that reduce T cell suppression in the TME. CAF and monocyte remodeling is an area of increasing interest, and ongoing preclinical studies aim to better understand the biology of individual monocyte and CAF subsets in an effort to develop new drugs to enhance their T cell activation capacity. apCAF, antigen-presenting cancer-associated fibroblast; CAF, cancer-associated fibroblast; FAK, focal adhesion kinase; iCAF, inflammatory cancer-associated fibroblast; myCAF, myofibroblastic cancer-associated fibroblast; PDAC, pancreatic adenocarcinoma; SHH, sonic hedgehog; TME, tumor microenvironment. Created in BioRender.

Recent advances in technologies and computational approaches have further defined subpopulations of inflammatory cells and fibroblasts that regulate T cell infiltration and function in PDACs. Myeloid-derived suppressor cells, Tregs, tumor-associated macrophages, B cells, neutrophils, mast cells, natural killer cells, and others have been shown to express suppressive chemokines, cytokines, and metabolites that reduce T cell function specifically in PDACs. Additionally, these can also be reprogrammed from tumor-supporting to T cell-enhancing cells. At least three subsets of cancer-associated fibroblasts (CAF) have been shown to participate in regulating PDAC inflammation. The inflammatory CAFs and myofibroblastic CAFs signal via tumor cells and different monocyte populations to prevent T cell entry and/or function. In contrast, antigen-presenting CAFs (apCAFs) are the smallest subset and have been shown to activate effector T cells and Tregs, depending on the ongoing type of PDAC inflammation. These apCAFs are being further analyzed to determine how to regulate their effector T cell activating function.1

Studies combining T cell activating agents with agents that reprogram one or more inflammatory/CAF cell populations within the TME are showing promise in turning on anti-PDAC T cell activity. For example, anti-PD-1 agents given with anti-CXCR4/CXCL12 pathway inhibitors can reverse CAF to monocyte cross-talk with improved T cell infiltration in metastatic PDAC. Agents targeting the CXCR2/CXCL5 axis can also intercept monocyte suppressive cross-talk. Current preclinical and clinical trials are continuing to identify the best combinations of agents that induce the most ‘fit’ T cells while reprogramming the critical suppressive mechanisms in PDACs.1

What is next

Immunotherapy works best in the neoadjuvant and adjuvant settings for immune responsive cancers. Efforts are currently underway testing neoantigen vaccines and immune checkpoint agents in these early disease settings in patients with PDAC. However, vaccine alone has not been successful, even in the adjuvant setting for PDAC. Although current approaches are testing vaccines with anti-PD-1 and/or anti-CTLA-4 and anti-CD137, T cell regulatory agents that target LAG-3, TIGIT, and CD134 (OX-40), which are also upregulated on PDAC T cells, should be considered. Additionally, metabolic pathways contribute to the heterogeneity and aggressiveness of PDAC, including glycolytic (mesenchymal subtype) and lipogenic (classical subtype) pathways. In addition, autophagy and mKRAS both induce micropinocytosis to support PDAC growth. Studies are just beginning to test combinations of immune modulators with metabolism-reprogramming agents.8 Developing modalities, such as T cell engagers and bispecific immune checkpoint modulators, may enhance T cell activation if these engagers can be targeted to PDAC antigens or relevant PDAC TME pathways.

Another exciting area is immune interception to prevent preclinical lesions from transforming into invasive cancer. mKRAS is the first known oncogene activated in normal pancreatic cells that drives tumorigenesis in over 90% of PDACs, and these mutations are conserved throughout disease progression. The G12D, G12V, and G12R mutations are the most dominant. These mutations can be detected in the earliest premalignant lesions. A previous preclinical study showed that a KRAS vaccine targeting G12D halted progression from PanIN 1 to pancreatic cancer in 40% of mice genetically engineered to express KRASG12D and p53 mutations.2 This study, along with additional human data, has led to the development of the first mKRAS-targeted vaccine currently being tested in individuals at risk for developing PDAC.9 Immune interception approaches targeting other early changes in precancers are also under development. However, the best vaccine approach combined with safe modulators of the earliest premalignant inflammatory states requires further study before these strategies can achieve success.

We have also entered a new era of targeting mKRAS with small molecule inhibitors. Long thought to be an undruggable target, multiple pan-KRAS and mutation-specific inhibitors are showing unprecedented promise in early clinical trials in patients with PDAC. Like other small molecule drugs targeting cancer-specific genetic pathways, such as PARP inhibitors, patients often develop resistance and experience recurrence within 6–12 months. Mutations in KRAS are known to have multiple procarcinogenic inflammatory effects on the PDAC TME.10 The reduction of these cancer-supporting inflammatory signals through KRAS small molecule inhibitors presents new opportunities for combinations with KRAS-targeted immunotherapies, potentially leading to longer-lasting tumor control.

Finally, a major challenge for most cancers is their rapid evolution to reduce immune recognition in favor of tumor progression and metastasis. Computational approaches are rapidly evolving to analyze the exponentially accumulating data from TME studies. These approaches are uncovering compensatory cross-talk signals induced by therapy, which could serve as new targets for TME reprogramming. In addition, as these datasets continue to expand and include pretreatment and during-treatment ‘omic’ data, they are being used to predict precision-based treatments at an individual patient level.11 The long-term goal is to develop ‘digital’ twins that can predict the evolution of a patient’s tumor and provide a ‘designer’ immunotherapy.

In summary, the next decade is likely to witness a transformation in therapeutic options that will include immunotherapy for the treatment of all stages of PDAC. The optimization of mKRAS vaccines will complement mKRAS-targeted small drugs, with the goal of providing long-term durability and prevention from recurrence. Once proven safe, successful approaches must be applied to earlier stages of the disease to achieve potential cures. The ultimate goal is to identify the most effective vaccines for intercepting early stages of precancer development.

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References

Footnotes

  • Contributors The manuscript was conceived and written by EMJ. SYM critically reviewed and edited the manuscript. The figure was designed by SYM. EMJ is the guarantor.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests EMJ reports other support from Abmeta and Adventris, personal fees from Dragonfly, Neuvogen, CPRIT, Surge Tx, Mestag, Medical Home Group, HDTbio, and grants from Lustgarten, Genentech, BMS, NeoTx, and Break Through Cancer. EMJ is the Dana and Albert 'Cubby' Broccoli Professor of Oncology.

  • Provenance and peer review Commissioned; externally peer reviewed.