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Review

Cancer Research Frontiers. 2016 May; 2(2): 252-276. doi: 10.17980/2016.252

Recent Advancements in Pancreatic Cancer Immunotherapy

Ying Ma1,2,6, Huamin Wang3, Yan Yang2,6, Craig D. Logsdon4,5, Stephen E. Ullrich1,6,7, Patrick Hwu2,6, Anirban Maitra3, Cassian Yee1,2,6

Departments of 1Immunology, 2Melanoma Medical Oncology, 3Pathology, 4Cancer Biology, 5Gastrointestinal Medical Oncology, and 6the Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, and 7The University of Texas Graduate School of Biomedical Sciences at Houston, 1515 Holcombe Boulevard, Houston, TX 77030.

 

*Corresponding author: Ying Ma, MD, PhD, Department of Melanoma Medical Oncology / Immunology, Unit 904, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030; tel: 713-745-7412; fax: 713-563-3280; E-mail: yingma@mdanderson.org. Cassian Yee, MD, Department of Melanoma Medical Oncology / Immunology, Unit 904, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030; tel: 713-563-3750; fax: 713-563-3424; E-mail: cyee@mdanderson.org.

Citation: Ying Ma, et al. Recent Advancements in Pancreatic Cancer Immunotherapy. Cancer Research Frontiers. 2016 May; 2(2): 252-276. doi: 10.17980/2016.252

Copyright: @ 2016 Ying Ma, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing Interests: The authors declare no competing financial interests.

Received Feb 1, 2016; Revised May 6, 201; Accepted May 16, 2016. Published May 26, 2016

 

 

Abstract

The overarching goal of this review is to highlight the current progress of immunotherapy in pancreatic cancer. Despite all the efforts, pancreatic cancer remains a disease that is refractory to almost all therapies and immunotherapy for pancreatic cancer remains in its infancy. In this review, we summarize promising advances and major hurdles in developing immunotherapeutic strategies for pancreatic cancer as presented in recent publications and a clinical trial database. Notably, a combination regimen of chemotherapy followed by immunotherapy appears to be superior to chemotherapy alone, wherein chemotherapeutic agents may play a dual role by reducing overall tumor burden through direct killing of cancerous cells and by indirect release of pro-inflammatory molecules and tumor associated antigens which, when presented in an immunogenic fashion, may function as an in situ “vaccine”. Critically, the timing of administration of standard chemotherapy can markedly impact the induction of antitumor responses. We anticipate that among the gamut of combination immunotherapy and chemo-radiation therapies that are now being evaluated, we will eventually be able to optimize a regimen that can generate long-lasting responses and usher a new weapon in the fight against pancreatic cancer.

Key Words: pancreatic cancer; immunotherapy; tumor microenvironment

 

 

Introduction

Immunotherapy has emerged as a pillar (1) in cancer treatment through its gradual acceptance as standard of care for some liquid and solid tumor malignancies, such as: B cell leukemia (2), metastatic melanoma (3, 4) and Non-Small-Cell Lung Cancer (NSCLC) (5, 6), joining the ranks of conventional modalities such as surgery, chemo/radiation, and targeted therapies. While this era has witnessed remarkable success in immune-based therapies for B cell malignancies as well as more limited effects on solid tumor malignancies such as melanoma and NSCLC, advanced pancreatic cancer is a disease that remains refractory to almost all the therapies (7, 8). However evidence of success in other solid tumors and a renaissance in our understanding of pancreatic tumor biology has led to translational efforts to pioneer immune-based approaches for the treatment of pancreatic cancer that has been accompanied by significant progress in the field (9).

Here, we present a review of the literature and clinical databases, highlighting promising advances and major hurdles in immunotherapy of pancreatic cancer, in the hope that it may provide insight into potential combination immune-based strategies and a rational therapeutic window within which these approaches may be most effective.

 

Current therapies against pancreatic cancer

Pancreatic cancer is a devastating and almost uniformly lethal malignancy, notoriously resistant to most therapies. Over 90% of pancreatic cancers present as pancreatic ductal adenocarcinoma (PDAC). In 2015, ~48,960 people in the United States will be diagnosed with this disease (10). Because of the aggressive nature of this cancer, the annual mortality rates closely match the incidence rate, and it is expected that ~40,000 will die from PDAC in the same year, with a 6% 5-year survival rate. For the 20% of patients with disease involving only the pancreas, surgical resection is the primary therapy. In the ~80% of patients with regional disease extension or metastases at presentation, chemotherapy is the primary treatment (11). Among the therapeutic options, polychemotherapy with infusional 5-fluorouracil (5-FU), leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus albumin-bound paclitaxel (nab paclitaxel) are commonly employed (11). Nab-paclitaxel is a cytotoxic agent that binds to overexpressed SPARC (Secreted Protein Acidic and Rich in Cysteine) in cancer cells and stroma in the PDAC tumor microenvironment (TME), thus increasing drug delivery and accumulation in tumor cells. As compared to gemcitabine alone, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate in metastatic PDAC, but rates of peripheral neuropathy and myelosuppression were increased (12). However, because of the inherent chemoresistance of PDAC, median progression-free survival (PFS) with these intensive regimens is ≤ 6 months (12, 13). Approximately 45% of patients who receive such first-line regimens are alive and sufficiently fit to receive second-line therapy (12, 13), but only a few therapies have been approved by the Food and Drug Administration (FDA) for such patients. On October 22, 2015 the U.S. FDA approved Onivyde (irinotecan liposome injection), in combination with fluorouracil and leucovorin, to treat patients with advanced (metastatic) pancreatic cancer who have been previously treated with gemcitabine-based chemotherapy. Onivyde represented a nanotherapeutic version of chemotherapy that directly delivers the agent to the tumor microenvironment and prolongs the active drug uptake. Recent results from these pilot studies demonstrated promise for pancreatic cancer with increased median survival for 2 months (14). Despite off-label use of existing chemotherapeutic agents, survival at 2 years is < 10%. Thus, while antitumor benefit has been observed with such regimens, toxicity is substantial and therapeutic options are limited. Novel, less toxic approaches are desperately needed for this lethal cancer, particularly in patients who experience failure of existing first-line therapies. Despite these efforts, the best supportive care and treatment regimens for patients with pancreatic cancer can only prolong survival for a few months, with the goal of achieving palliation rather than cure (15).

 

Tumor microenvironment (TME) is a barrier to immune infiltration in pancreatic cancer

In the multistep progression of PDAC, the emergence of initiating genetic events within neoplastic cells, such as oncogenic KRAS mutations, is subsequently sculpted by additional pressures in the TME, including co-opting of the innate and adaptive arms of the host immune system (16). The importance of the TME in the biology of this disease, as well as a potential substrate for therapy, has become increasingly recognized (17-19). PDAC exists in a complex desmoplastic stroma that provides a structural framework for tumor growth, and conceals the tumor cells from immune surveillance. Tumor-associated stroma comprises a mix of fibroblasts (myofibroblasts and pancreatic stellate cells) and an abundance of immunosuppressive regulatory T cells (Tregs), myeloid derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and mast cells (20-22) that restrain immunologically-mediated tumor cell killing (23). PDAC cells secrete chemokines that recruit this myriad of immune suppressor cells to the TME, which are then activated either by direct contact, or by cancer cell–derived triggers to selectively release additional tumor-promoting mediators (17, 20). In preclinical models, genetic or pharmacological modulation of either the number, or function, of immune suppressor cells in the TME has been shown to decrease the growth of PDAC (24-26). However, none of these approaches have yet made their way into the clinic, and therefore, single-agent immunotherapy approaches attempted to date, such as checkpoint inhibitors or vaccines, have been at best modestly successful (27-33). In contradistinction to melanoma, PDAC has long been considered a “non-immunogenic” neoplasm, in part due to the formidable barrier of the TME. Converting a non-immunogenic PDAC into an “immunogenic” neoplasm may create a treatment window for judicious application of immunotherapeutic strategies (30, 34, 35).

 

Current strategies in cancer immunotherapy

With great strides in the understanding of immunology and cancer biology over the past 20 years, cancer immunotherapy has emerged as a model for successfully translating scientific discovery from the laboratory to the clinical arena. Effective immunotherapies have mediated durable antitumor immune response and cancer regressions, leading to remarkable prolongation in the survival of patients with leukemia, melanoma, lung cancer, liver, bladder, ovarian, renal, and prostate cancers (36). On the heels of these studies, immunotherapy may be poised to revolutionize in similar fashion the treatment of pancreatic cancer. We summarize below the current immunotherapeutic strategies for human cancers in Table 1.

 

Current clinical trials for pancreatic cancer

Pancreatic cancer mouse models provide an entry point for the study of immunotherapy in this disease. Syngeneic orthotopic pancreatic cancer allograft mouse models assessing the potency of immune reagents have demonstrated the ability to eliminate small burdens of established tumors, a situation that recapitulates the condition of minimal residual disease commonly found after surgical removal of human tumors (37). In an example of this approach, we have demonstrated that by stabilizing the mast cell membrane, we are able to cure mice with pre-established pancreatic cancer by blocking immunosuppression and unleashing an enhanced endogenous anti-tumor immune response (20, 21).

Genetically engineered mouse models (GEMM) that yield spontaneous PDAC have led to renewed enthusiasm to exploring potential therapies with a mechanistic perspective. A commonly used, well-validated, clinically relevant model, using KrasG12D;Trp53R172H;Pdx1-Cre (KPC) mice (48), can recapitulate the heterogeneity of tumorigenesis and the TME of human PDAC. Similar to the clinical scenario among patients, these mice are largely resistant to conventional therapies allowing the full spectrum of current immunotherapy strategies to tested in this model; however, with only sporadic success. To date, there is no FDA approved immunotherapeutic regimen for the specific treatment of pancreatic cancer. On the basis of additional studies using novel immune modulatory combinations, in multiple pre-clinical PDAC models, a new wave of clinical trials was launched. In the following Tables 2-16, we surveyed the database of clinicaltrials.gov to identify the most recent immune-based clinical regimens. The key words used in the search included: immune, immunotherapy, vaccine, antibody, antigen, CTLA-4, PD-1, tumor infiltrating lymphocyte (TIL), IDO, CAR-T, mesothelin.

 

CD40 agonist trials

As a member of the tumor necrosis factor receptor superfamily, CD40 is expressed on the cell surface of immune cells, in particular B cells, dendritic cells, macrophages and monocytes as well as some normal and malignant cells. Binding of CD154 (the primary ligand for CD40) on T cell surface, CD40 activates T cells by ligand-receptor direct interaction. In addition, this binding indirectly activated T cells by CD154 mediating cytokine release from dendritic cells and macrophages (49). Anti-CD40 agonist antibodies induce tumor regression by both stimulating T cell activation (T-cell-dependent) and macrophage reprogramming (T-cell-independent) (50). It is believe that the T-cell-independent mechanism is related to turnaround of the pro-tumorigenic macrophage and interference of the desmoplastic tumor stroma in PDAC. Several trials (see Table 2) using agonistic CD40 monoclonal antibody CP-870,893 (51) have demonstrated effective anti-tumor activity in PDAC patients.

 

GVAX and CRS-207

GVAX is a vaccine comprised of tumor cells transfected with GM-CSF, which recruits and activates dendritic cells (DCs) in vivo. As highly efficient T-cell activator, DCs in the TME is required for stimulating a robust adaptive anti-tumor immune response due to its ability to present tumor-associated antigens to T cells and maintain the antigen-specific T cell potency (38). CRS-207 (52) is a live-attenuated recombinant Listeria monocytogenes bacterium engineered to express human mesothelin that was overexpressed in pancreatic cancerous ducts but not in pancreatitis and normal tissues. CRS-207 is capable of both delivering mesothelin antigen into both class I and II antigen-processing pathways to induce tumor-specific T cell response and triggering cytokine release to boost natural killer (NK) cell activation. As a whole-cell vaccine platform, GVAX and CRS-207 form a potent sequential 2-vaccine program. On the basis of safety, feasibility, and immune activation (53) with GVAX plus CRS-207, other regimens, such as chemo/radiotherapy, checkpoint control antibodies were introduced to the trials to maximize the efficacy. GVAX in conjunction with immunomodulatory cyclophosphamide (54) has been applied to many preclinical tumor models and several human cancers as the low dose cyclophosphamide serves as a vaccine enhancer in disrupting immune tolerance through depleting regulatory T cell in situ and promoting dendritic cell maturation. Indeed, heterologous prime/boost with GVAX and CRS-207 in pancreatic patients conditioned with cyclophosphamide extended survival with minimal toxicity (28). Recent trials involving this combinational vaccine approach are listed in Table 3. Chemotherapy, such as Folfirinox, or radiation therapy, such as high-energy X rays, work in different ways to kill tumor cells and are being tested in these trials with GVAX/CRS-207/Cyclophosphamide combination therapy. In addition, checkpoint control antibodies, such as anti-PD-1 and anti-CTLA-4, are the most current immunotherapeutic regimens for boosting pre-existent anticancer immunity initiated by GVAX/CRS-207/Cyclophosphamide combination therapy.

 

G17DT

Transgenic, hypergastrinemic InsGas mice (56) were developed to express human CCK2 receptor for investigating the role of gastrin/CCK in pancreatic exocrine cells. Because gastrin and its receptors are co-expressed on human pancreatic adenocarcinoma, this mouse model validated the mitogenic potency of gastrin peptides. When it was discovered that intramuscular injection of gastric antigens can generate an immune response, clinical trials were initiated to exploit the use of this target for eliciting an antitumor response. G17DT, an antigastrin immunogen, can produce neutralizing antibodies against the tumor growth factors amidated and glycine-extended form of gastrin-17 (57). Rapid and sustained antibody production after immunization with G17DT can generate a robust anti-tumor response, thus, G17DT may represent a new therapeutic option for responders with pancreatic cancer (Table 4).

CEA/MUC-1

CEA (carcinoembryonic antigen, an oncofetal antigen) and MUC-1 (mucin, a highly glycosylated protein) are expressed at high levels on most human pancreatic cancers. T cells can recognized HLA-restricted epitopes derived from CEA and non-HLA-restricted epitopes encoded by MUC-1 (58, 59). A vaccine, engineered with poxviruses targeting both CEA and MUC-1, can generate polyclonal T cells, which produce antigen-specific anti-tumor effects and appear to prevent tumor escape during antigen loss. This vaccination protocol has proven to be safe and well tolerated (60) with some significant response, as indicated in Table 5.

 

Algenpantucel-L

A cell-based allogeneic pancreatic cancer vaccine, algenpantucel-L, targets alpha-1,3 galactosyl epitopes to induce better antitumor immune priming on the concept of the hyperacute rejection response. This vaccine was engineered to express alpha-Gal (murine alpha-1,3-galactosyltransferase gene) in two human pancreatic ductal adenocarcinoma cell lines (HAPa-1 and HAPa-2). Since alpha-Gal is inactive in normal human cells, Algenpantucel-L xenotransplantation will produce high titer of anti-alpha-Gal antibodies that trigger hyperacute rejection presenting as complement-mediated tumor cell lysis and antibody-dependent cell-mediated cytotoxicity (61). Through the subsequent opsonization and phagocytosis of the whole tumor cells, APCs will process and present the entire library of TAAs to cytotoixic effector T cells to fight the patient’s own cancer. Algenpantucel-L has demonstrated survival benefit for pancreatic cancer patients in a Phase II trial for patients with surgically resected disease. The results shown in Table 6 reflect improved survival in patients when compared with a historical control (62) in phase II studies which remain to be proven in randomized Phase III trials (currently accruing).

 

Bruton’s Tyrosine Kinase inhibitor

The first clinically approved use of ibrutinib, a novel BTK inhibitor developed by Pharmacyclics, has led to decreased mouse tumor growth and improved responsiveness to gemcitabine in orthotopic pancreatic cancer mouse models (64). In another preclinical study, Ibrutinib improved the survival of both genetically engineered PDAC models, as well as mice bearing patient-derived PDAC xenografts (65). Ibrutinib therapy also reduced the stromal desmoplasia in preclinical models, and improved delivery of chemotherapeutics to the tumor milieu. Inhibiting BTK has the desired effect of inhibiting mast cell degranulation and cytokine secretion, a result that our group and others have shown, mediating tumor suppression in PDAC (20-22). However, Ibrutinib suffers from multiple off-target effects that limit its application in solid tumors where enhancing effector T-cell function is a crucial intent (2). Ibrutinib’s potency on ITK (IL2-inducible T-cell kinase) and TXK (Tyrosine-protein Kinase) may explain why it interferes with cell-mediated anti-tumor activities and immune-mediated killing in the TME.

 

Acerta Pharma has developed ACP-196, an orally bioavailable, 2nd generation inhibitor of Bruton’s tyrosine kinase (BTK). BTK is a non-receptor enzyme in the Tec kinase family that is expressed by cells of hematopoietic origin, including B cells, myeloid cells, and mast cells, where it regulates multiple cellular processes, including proliferation, differentiation, apoptosis, and cell migration (66-68). In addition, BTK-dependent activation of mast cells, myeloid cells and other immunocytes in the peritumoral inflammatory stroma has been shown to sustain the complex microenvironment needed for solid tumor maintenance (69-71). Overall, BTK inhibition interferes with the cross-talk between neoplastic cells and the TME, such as immune regulatory cells recruitment and infiltration into tumor, suggesting disruption of intrinsic and extrinsic survival signals (70, 72). Importantly, unlike Ibrutinib, ACP-196 did not inhibit ITK or TXK, which are both involved in Teff function (73-75). Two ongoing trials at MD Anderson Cancer Center (Table 7) will evaluate whether the combination therapy of BTK inhibition and checkpoint blockade leads to greater benefit compared with monotherapy.

 

Immune checkpoint control antibodies

The activation and inhibition of the immune system are controlled through signals from a panel of ligands and receptors of co-stimulatory and co-inhibitory molecules, which have been recognized as immune checkpoint control pathways. Anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies have been applied in cancer immunotherapy for interfering with the inhibitory signaling in T cells (76). By rescuing anti-tumor immune responses, these antibodies can mediate durable cancer regressions and long-term survival (77).

 

CTLA-4

CTLA-4 (cytotoxic T lymphocyte antigen 4) (77-79), a costimulatory molecule similar to CD28, is expressed on activated T cells and also bind to the ligands CD80 (B7-1) and CD86 (B7-2) on antigen-presenting cells. CD28 molecule is constitutively expressed on T cell surface and stimulating T cell activation through binding to the ligands, whereas CTLA-4 can transmit an inhibitory signal due to compete for CD28 binding to CD80/86. Anti-CTLA-4 antibody, via blocking the high affinity binding of CTLA-4 to CD80/86, allows CD28 to interact with CD80/86. In patients with melanoma (80), anti-CTLA-4 can magnify anti-tumor response induced by the neoepitopes from tumor mutations. By releasing the “brake” on T cell activation (81), CTLA-4 blockade expands immunological memory and boosts long-lasting immunogenicity. Ipilimumab anti-CTLA-4 IgG1 antibody gained FDA-approval for second-line treatment of patients with metastatic melanoma. Trials incorporating combination regimens in Table 8 are being tested in patients with pancreatic cancer. Tremelimumab (82) anti-CTLA-4 IgG2 antibody achieved survival benefit for 9 patients with pancreatic cancer when combined with gemcitabine in a phase I trial, and its subsequent combination regimens were under the trials in Table 8.

 

PD-1/PD-L1

PD-1 (84) is an inhibitory receptor that down-regulates T-cell activation when bound to a PD-L1 or PD-L2 ligand on tumor cells. Notably, for patients with melanoma with positive expression of the PD-1 ligand, anti–PD-1 immunotherapy has been associated with a better response (85). Nivolumab (86), a fully humanized immunoglobulin G4 (IgG4) mAb targeting human PD-1 with high affinity, has been approved by FDA for treatment on melanoma and lung cancer. There was no difference in the overall median survival rate for nivolumab or nivolumab and ipilimumab combined, but among patients with PD-1 ligand–negative tumors, progression-free survival was longer with the combination therapy of nivolumab and ipilimumab than with nivolumab alone (3). In light of these promising results in melanoma, PD-1/PD-L1 blockades are being evaluated in several clinical trials (see Table 9) involving combination/chemotherapy regimens for the treatment of patients with pancreatic cancer.

 

Adoptive T cell therapy

Adoptive T-cell therapy (42) involves the ex vivo enrichment and expansion of tumor-reactive T cells for infusion. As an immune-based approach, adoptive therapy has become an increasingly attractive modality for the treatment of patients with cancer due to its potential for high specificity, non-cross resistance with conventional therapies, and the promise of long-term immunoprotection. Adoptive cellular therapy encompasses the use of tumor reactive T cells derived from an endogenous source (tumor infiltrating lymphocytes, TIL or peripheral blood) or a genetically modified lymphocyte population engineered to recognize tumor antigen through expression of the cognate chimeric antibody or T-cell receptor (CAR/TCR).

 

Tumor Infiltrating Lymphocyte (TIL)

To date, only TIL therapies have been reported for the treatment of pancreatic cancer, as shown in Table 10, although efforts are underway in our lab and others to explore the use of MS/MS and RNAseq analysis of patient tumor immunopeptidome to develop T cell therapy targeting autologous tumor neo-epitopes for pancreatic cancer.

 

CAR-T cells

Adoptive therapy with T cells transduced to express chimeric antigen receptors (CAR) consisting of fusion proteins joining antibody variable regions to T-cell signaling chains. The antibody moiety confers antigen specificity and activates the T cell signaling generally in tandem with the cytoplasmic signaling domains of CD28, 4-1BB and other costimulatory molecules (44-46). CAR-T cell represents an important modality with the promise of off-the-shelf strategies for the treatment of pancreatic cancer. The following clinical trials in Table 11 are being evaluated for use in several solid tumor malignancies including pancreatic cancer (46).

 

IDO inhibitor

Indoleamine 2,3-dioxygenase (IDO), which is overexpressed in metastatic PDAC (87), contributes to the immune suppressive tumor microenvironment by starving T lymphocytes of tryptophan (87). Active IDO enzyme can catalyze L-tryptophan (L-Trp) into kynurenine (Kyn) pathway metabolites. In PDAC, L-Trp was completely consumed by tumor cell-derived IDO, resulting in the significant reduction of L-Trp concentration in TME. In response to L-Trp deficiency, tumor infiltrating CD8+ T cells will be subjected to cell cycle arrest and anergy through mTOR (mammalian target of rapamycin) and PKC signaling pathways. IDO inhibitors may restore L-Trp level and overcome the immune suppressive TME in vivo (88). Clinical grade IDO inhibitors are currently undergoing evaluation in solid tumors, including pancreatic cancers listed in Table 12.

 

Mesothelin

Mesothelin is a tumor antigen upregulated on most human pancreatic cancer. Although the normal function of membrane-bound mesothelin is still unknown, the soluble mesothelin (89) can be detected in the peripheral blood of patients with pancreatic cancer, intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm, but not in healthy individuals. Mesothelin specific antibody and T-cell response in those patients indicated antimesothelin immunity and offered potential therapy against pancreatic cancer. In addition to mesothelin vaccine trials using GVAX and CRS-207 in combination (28), antibodies (90) against mesothelin provide an alternative for pancreatic cancer immunotherapy, as shown in Table 13.

 

Dendritic cell

As a professional antigen-presenting cell, dendritic cells (DCs) play an essential role in the anti-tumor immune response with their capacity to capture, process, and present antigens to T cells (91). DCs are extremely efficient for vaccination by priming naïve CD8+ T cells into cytotoxic T cells as well as cytokine release (92). In addition to the vaccine related studies listed in the above Tables, we list a broad spectrum of DC vaccine trials in Table 14. In addition to shaping the specificity of response against tumor antigens through DC vaccination, these trials also focus on modifying the function and activation of dendritic cells. In the immune-privileged microenvironment of pancreatic cancer, insufficiency of dendritic cells is the main roadblock for T cell activation, a typical malfunction observed in many other cancer types (93). Dendritic cell expansion and maturation may overcome the resistance to checkpoint immunotherapy and reprogram the TME to an immunogenic microenvironment (93).

 

Ras

The oncogenic Ras mutation is an essential and initiating event in pancreatic tumorigenesis (48). Preclinical studies (94) demonstrated that Kras mutation is required for PDAC maintenance. Targeting oncogenic/mutant Ras may provide a novel therapeutic avenue for pancreatic cancer, and the ongoing trials that are associated with Ras targeting are summarized in Table 15. Notably, the long-term follow-up (over 10 years) of twenty-three patients who were vaccinated after surgical removal of pancreatic adenocarcinoma (22 pancreaticoduodenectomies, one distal resection), in two Phase I/II clinical trials (95, 96), showed great promise on correlation of sustained immunological T-cell reactivity and prognosis. The mechanism of the vaccine was attributed to the long synthetic mutant ras peptides designed primarily to trigger T-helper responses. Seventeen of 20 evaluable patients (85%) responded immunologically to the vaccine. Median survival for all patients was 27.5 months and 28 months for immune responders. The 5-year survival was significantly improved to 22% and 29%, respectively. Strikingly, 10-year survival was 20% (four patients out of 20 evaluable) versus zero (0/87) in a cohort of non-vaccinated patient treated in the same period. Three patients presented a memory response up to 9 years after vaccination. The encouraging milestone of long-term immune response together with 10-year survival following surgical resection indicates that vaccination against oncogenic/mutant K-ras may boost the effect of surgery and represent an adjuvant alternative for future treatment (97).

 

Combination of chemotherapy and immunotherapy

Chemotherapy with gemcitabine has been the standard first-line treatment for patients with unresectable locally advanced or metastatic pancreatic cancer for 18 years (99). Since 2013, chemotherapy with nab-paclitaxel plus gemcitabine has significantly improved overall survival, progression-free survival, and response rate in patients with metastatic pancreatic adenocarcinoma as compared with gemcitabine alone (12). Unfortunately, the improved median survival is only 8.5 months. The strength of combination with chemotherapy and immunotherapy is being tested in animal models.

 

It has been recognized that an optimized approach combining anti-cancer vaccination with chemotherapy and/or radiation therapy is urgently needed. The use of vaccines is also a compelling approach for maintenance therapy of patients who are grossly disease-free, or whose disease is at least stabilized, upon chemotherapy and/or radiation therapy. Prime-boost vaccination strategies, in particular those that use Listeria vaccines for boosting, are a promising approach for maintenance therapy (100).

 

In preclinical studies, combination therapy of chemotherapy followed by immunotherapy is superior to chemotherapy alone. In these in vivo tests, chemotherapeutic agents played a dual role. On one hand, they reduced overall tumor burden by direct killing of cancer cells; on the other hand, they indirectly lead to the release of pro-inflammatory molecules and tumor associated antigens (101), which may be functioning as a “vaccine” by presumably releasing tumor antigens in an immunogenic fashion. This may potentially explain the improved efficacy of CD40 agonists when given after, but not before, chemotherapy (102). This synergistic efficacy is also observed with combined chemotherapy using anti-CD47 antibody (103). Notably, there might be a limited window of time when chemotherapy drugs can be effective, yet without blunting anti-tumor immunity (103).

 

In contrast, chemotherapy administered after immunotherapy had detrimental effects on development of beneficial antitumor memory immune responses. Chemotherapy administered after anti-CD47 treatment did not result in faster tumor regression than anti-CD47 alone. Chemotherapy can suppress the immune system and kill recently activated immune cells including memory cells. The ultimate consequence of this sequence is to destroy the therapeutic effects of immunotherapy (103). In addition, recent clinical studies have experimented using the sequential administration of anti-cancer vaccines and chemotherapy/radiation; however, the immunosuppressive effects of these standard cytotoxic regimens may compromise the efficacy of immunotherapy. Thus, the timing of administration of standard chemotherapy markedly impacted the induction of antitumor responses by immune-based therapy.

 

Combination of radiation therapy (radiotherapy) and immunotherapy

The most recent advancement of radiation technology, including intensity modulated radiation therapy, stereotactic radiosurgery, proton therapy, antibody-radionuclide conjugates, has been applied to cancer therapy for 20 years (104). Radiotherapy is based on the ionizing energy causing DNA damage to induce direct tumor cell death, such as apoptosis, mitotic catastrophe, or necrosis, along with the cascade events in tumor microenvironment (TME) (105). The best efficacy of radiotherapy will not only rely on the direct tumor cell death, but also the contribution of intrinsic anti-tumor immune response. The damage-associated molecular patterns in TME trigger immune sensors such as toll-like receptors (TLR) (104) which serve as the link between radiation and immune properties. The damaged tumor cells up-regulated tumor-associated antigens (TAA), recruited dendritic cell migration and maturation, and induced T effector cells to TME for removing the residual tumor cells. One of the cascade events in TME is abscopal effect, a poorly understood phenomenon that radiation can induce tumor regression outside the exposure area of radiation. Recent progress in immunology allowed researcher to demonstrate that abscopal effect is immune mediated and T cell dependent (106) peripheral clonal expansion, warranting further immune intervention in this setting of cancer therapy. Indeed, combination of immunotherapy with radiation therapy has improved cancer treatment through synergy (107). Trials (104) with TLR agonists and radiation therapy have been tested in patients with lymphoma, breast cancer, prostate cancer, etc. The superiority (108, 109) of radiation and anti-CTLA-4 and anti-PD-1 therapy is confirmed in preclinical melanoma models, although the mechanism of TCR repertoire diversity and tumor heterogeneity remains unknown. In the near future, it might be possible that radiation can turn pancreatic cancer from an immune privileged tumor microenvironment to an immune active state. Radioimmunotherapy (110) for pancreatic cancer may emerge as a novel regimen (111) complementing to the multimodality tumor directed therapy.

 

Perspectives and Conclusion

The principal goal of this review is to highlight current progress of immunotherapy in pancreatic cancer. The seminal advantages that immunotherapy bring to the treatment of pancreatic cancers are: (1) The ability to broaden and encompass greater numbers of patients eligible for treatment and to achieve a personalized approach to medicine by using the autologous cancer antigens as a means of generating a populations antigen-specific effector cells. (2) A means to trigger T cell memory and retain long-term remission. (3) A means to modulate the immune microenvironment for example through targeted therapies to mitigate desmoplasia, a physical barrier where pancreatic cancer stem cells may be sequestered. (4) The development of novel Immune adjuvants defined through mouse models, that may reverse the noxious immune suppressive tumor microenvironment, a functional barrier of pancreatic cancer. (5) Immune reagents that potentiate the penetrance of chemotherapeutic reagents and improve drug delivery. It is hoped that multiple possible avenues to developing a deeper understanding of immune resistance, T cell persistence, mechanisms of immune checkpoint inhibition and vaccination strategies, will allow us to chart a strategy that exploits the potential of the immune system to eradicate the refractory disease and maintain a durable clinical response in patients with pancreatic cancer.

 

Abbreviations:

5-FU, fluorouracil

ADCC, antibody-dependent cell-mediated cytotoxicity

BiTE, bi-specific T-cell engager

BTK, Bruton’s tyrosine kinase

CAR, chimeric antigen receptors

CEA, carcinoembryonic antigen

CTLA-4, cytotoxic T lymphocyte antigen 4

Cy, cyclophosphamide

DART, dual-affinity re-targeting

DCs, dendritic cells

DFS, disease-free survival

FDA, Food and Drug Administration

GEMM, genetically engineered mouse models

GM-CSF, granulocyte-macrophage colony-stimulating factor

GVAX, granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting tumor vaccine or GVAX pancreatic cancer vaccine.

IDO, indoleamine 2,3-dioxygenase

IMiD, immunomodulating drug

IPMN, intraductal papillary mucinous neoplasm

ITK, IL2-inducible T-cell kinase

KPC, KrasG12D;Trp53R172H;Pdx1-Cre

Kyn, kynurenine

L-Trp, L-tryptophan

MDSC, myeloid derived suppressor cells

mTOR, mammalian target of rapamycin

MUC-1, mucin

NSCLC, Non-Small-Cell Lung Cancer

OS, overall survival

PD-1, programmed cell death protein 1

PD-L1, programmed death-ligand 1

PD, progressive disease

PDAC, pancreatic ductal adenocarcinoma

PFS, progression-free survival

PR, partial responses

SBRT, Stereotactic Body Radiation Therapy

SD, stable disease

SPARC, secreted protein acidic and rich in cysteine

TAA, tumor-associated antigens

TCR, T-cell receptor

Teff, effector T cells

TIL, tumor-infiltrating lymphocyte

TLR, toll-like receptors

TMAs, tumor-associated macrophages

TME, tumor microenvironment

Tregs, regulatory T cells

TXK, tyrosine-protein kinase

 

References

  1. Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015 Apr 3;348(6230):56-61. DOI: 10.1126/science.aaa8172.
  2. Byrd JC, Harrington B, O’Brien S, Jones JA, Schuh A, Devereux S, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jan 28;374(4):323-32. DOI: 10.1056/NEJMoa1509981.
  3. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34. DOI: 10.1056/NEJMoa1504030.
  4. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. DOI: 10.1056/NEJMoa1503093.
  5. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. DOI: 10.1056/NEJMoa1507643.
  6. Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. DOI: 10.1056/NEJMoa1504627.
  7. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 2008 Jun 19;358(25):2698-703. DOI: 10.1056/NEJMoa0800251.
  8. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015 Apr 3;348(6230):62-8. DOI: 10.1126/science.aaa4967.
  9. Palucka K. Q&A: Evidence presenter. Interview by Marian Turner. Nature. 2013 Dec 19;504(7480):S9. DOI: 10.1038/504S9a.
  10. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015 Jan-Feb;65(1):5-29. DOI: 10.3322/caac.21254.
  11. Tempero MA, Malafa MP, Behrman SW, Benson AB, 3rd, Casper ES, Chiorean EG, et al. Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2014 Aug;12(8):1083-93.
  12. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013 Oct 31;369(18):1691-703. DOI: 10.1056/NEJMoa1304369.
  13. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817-25. DOI: 10.1056/NEJMoa1011923.
  14. Dawood S. Updates from Gastrointestinal ASCO 2015. Indian J Med Paediatr Oncol. 2015 Apr-Jun;36(2):133-6. DOI: 10.4103/0971-5851.158852.
  15. Marks E, Saif MW, Jia Y. Updates on first-line therapy for metastatic pancreatic adenocarcinoma. JOP. 2014 Mar;15(2):99-102. DOI: 10.6092/1590-8577/2279.
  16. Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv Immunol. 2006;90:1-50. DOI: 10.1016/S0065-2776(06)90001-7.
  17. Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA. The pancreas cancer microenvironment. Clin Cancer Res. 2012 Aug 15;18(16):4266-76. DOI: 10.1158/1078-0432.CCR-11-3114.
  18. Rucki AA, Zheng L. Pancreatic cancer stroma: understanding biology leads to new therapeutic strategies. World J Gastroenterol. 2014 Mar 7;20(9):2237-46. DOI: 10.3748/wjg.v20.i9.2237.
  19. Wilson JS, Pirola RC, Apte MV. Stars and stripes in pancreatic cancer: role of stellate cells and stroma in cancer progression. Front Physiol. 2014;5:52. DOI: 10.3389/fphys.2014.00052.
  20. Ma Y, Hwang RF, Logsdon CD, Ullrich SE. Dynamic mast cell-stromal cell interactions promote growth of pancreatic cancer. Cancer Res. 2013 Jul 1;73(13):3927-37. DOI: 10.1158/0008-5472.CAN-12-4479.
  21. Ma Y, Ullrich SE. Intratumoral mast cells promote the growth of pancreatic cancer. Oncoimmunology. 2013 Oct 1;2(10):e25964. DOI: 10.4161/onci.25964.
  22. Chang DZ, Ma Y, Ji B, Wang H, Deng D, Liu Y, et al. Mast cells in tumor microenvironment promotes the in vivo growth of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2011 Nov 15;17(22):7015-23. DOI: 10.1158/1078-0432.CCR-11-0607.
  23. Shibuya KC, Goel VK, Xiong W, Sham JG, Pollack SM, Leahy AM, et al. Pancreatic ductal adenocarcinoma contains an effector and regulatory immune cell infiltrate that is altered by multimodal neoadjuvant treatment. PLoS One. 2014;9(5):e96565. DOI: 10.1371/journal.pone.0096565.
  24. Clark CE, Hingorani SR, Mick R, Combs C, Tuveson DA, Vonderheide RH. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007 Oct 1;67(19):9518-27. DOI: 10.1158/0008-5472.CAN-07-0175.
  25. Nagaraj S, Youn JI, Weber H, Iclozan C, Lu L, Cotter MJ, et al. Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer. Clin Cancer Res. 2010 Mar 15;16(6):1812-23. DOI: 10.1158/1078-0432.CCR-09-3272.
  26. Cotechini T, Medler TR, Coussens LM. Myeloid Cells as Targets for Therapy in Solid Tumors. Cancer J. 2015 Jul-Aug;21(4):343-50. DOI: 10.1097/PPO.0000000000000132.
  27. Le DT, Lutz E, Uram JN, Sugar EA, Onners B, Solt S, et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunother. 2013 Sep;36(7):382-9. DOI: 10.1097/CJI.0b013e31829fb7a2.
  28. Le DT, Wang-Gillam A, Picozzi V, Greten TF, Crocenzi T, Springett G, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015 Apr 20;33(12):1325-33. DOI: 10.1200/JCO.2014.57.4244.
  29. Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science. 2011 Mar 25;331(6024):1612-6. DOI: 10.1126/science.1198443.
  30. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014 Jun 16;25(6):719-34. DOI: 10.1016/j.ccr.2014.04.005.
  31. Stromnes IM, Brockenbrough JS, Izeradjene K, Carlson MA, Cuevas C, Simmons RM, et al. Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut. 2014 Nov;63(11):1769-81. DOI: 10.1136/gutjnl-2013-306271.
  32. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012 Mar 20;21(3):418-29. DOI: 10.1016/j.ccr.2012.01.007.
  33. Rajeshkumar NV, Dutta P, Yabuuchi S, de Wilde RF, Martinez GV, Le A, et al. Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function. Cancer Res. 2015 Aug 15;75(16):3355-64. DOI: 10.1158/0008-5472.CAN-15-0108.
  34. Lutz ER, Wu AA, Bigelow E, Sharma R, Mo G, Soares K, et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol Res. 2014 Jul;2(7):616-31. DOI: 10.1158/2326-6066.CIR-14-0027.
  35. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014 Jun 16;25(6):735-47. DOI: 10.1016/j.ccr.2014.04.021.
  36. Kirkwood JM, Butterfield LH, Tarhini AA, Zarour H, Kalinski P, Ferrone S. Immunotherapy of cancer in 2012. CA Cancer J Clin. 2012 Sep-Oct;62(5):309-35. DOI: 10.3322/caac.20132.
  37. Greten TF, Jaffee EM. Cancer vaccines. J Clin Oncol. 1999 Mar;17(3):1047-60.
  38. Salman B, Zhou D, Jaffee EM, Edil BH, Zheng L. Vaccine therapy for pancreatic cancer. Oncoimmunology. 2013 Dec 1;2(12):e26662. DOI: 10.4161/onci.26662.
  39. Rossi DL, Rossi EA, Cardillo TM, Goldenberg DM, Chang CH. A new class of bispecific antibodies to redirect T cells for cancer immunotherapy. MAbs. 2014 Mar-Apr;6(2):381-91. DOI: 10.4161/mabs.27385.
  40. Carmi Y, Engleman EG. Tumor-binding antibodies and tumor immunity. Oncotarget. 2015 Nov 3;6(34):35129-30. DOI: 10.18632/oncotarget.4889.
  41. Winograd R, Byrne KT, Evans RA, Odorizzi PM, Meyer AR, Bajor DL, et al. Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma. Cancer Immunol Res. 2015 Apr;3(4):399-411. DOI: 10.1158/2326-6066.CIR-14-0215.
  42. Yee C. The use of endogenous T cells for adoptive transfer. Immunol Rev. 2014 Jan;257(1):250-63. DOI: 10.1111/imr.12134.
  43. Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science. 2015 Oct 16;350(6258):aab4077. DOI: 10.1126/science.aab4077.
  44. Hwu P, Shafer GE, Treisman J, Schindler DG, Gross G, Cowherd R, et al. Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the Fc receptor gamma chain. J Exp Med. 1993 Jul 1;178(1):361-6.
  45. Hwu P, Yang JC, Cowherd R, Treisman J, Shafer GE, Eshhar Z, et al. In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes. Cancer Res. 1995 Aug 1;55(15):3369-73.
  46. Hwu P. CCR 20th Anniversary Commentary: Chimeric Antigen Receptors-From Model T to the Tesla. Clin Cancer Res. 2015 Jul 15;21(14):3099-101. DOI: 10.1158/1078-0432.CCR-14-2560.
  47. Laheru D, Jaffee EM. Immunotherapy for pancreatic cancer – science driving clinical progress. Nature reviews Cancer. 2005 Jun;5(6):459-67. DOI: 10.1038/nrc1630.
  48. Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell. 2003 Dec;4(6):437-50. DOI: S153561080300309X [pii].
  49. Schonbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci. 2001 Jan;58(1):4-43.
  50. Vonderheide RH, Bajor DL, Winograd R, Evans RA, Bayne LJ, Beatty GL. CD40 immunotherapy for pancreatic cancer. Cancer Immunol Immunother. 2013 May;62(5):949-54. DOI: 10.1007/s00262-013-1427-5.
  51. Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clin Cancer Res. 2013 Mar 1;19(5):1035-43. DOI: 10.1158/1078-0432.CCR-12-2064.
  52. Le DT, Brockstedt DG, Nir-Paz R, Hampl J, Mathur S, Nemunaitis J, et al. A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction. Clin Cancer Res. 2012 Feb 1;18(3):858-68. DOI: 10.1158/1078-0432.CCR-11-2121.
  53. Laheru D, Lutz E, Burke J, Biedrzycki B, Solt S, Onners B, et al. Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res. 2008 Mar 1;14(5):1455-63. DOI: 10.1158/1078-0432.CCR-07-0371.
  54. Antonarakis ES, Carducci MA. Combining low-dose cyclophosphamide with GM-CSF-secreting prostate cancer immunotherapy enhances antitumor immune effects. Expert Opin Investig Drugs. 2010 Feb;19(2):311-4. DOI: 10.1517/13543780903530678.
  55. Lutz E, Yeo CJ, Lillemoe KD, Biedrzycki B, Kobrin B, Herman J, et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation. Ann Surg. 2011 Feb;253(2):328-35. DOI: 10.1097/SLA.0b013e3181fd271c.
  56. Clerc P, Saillan-Barreau C, Desbois C, Pradayrol L, Fourmy D, Dufresne M. Transgenic mice expressing cholecystokinin 2 receptors in the pancreas. Pharmacol Toxicol. 2002 Dec;91(6):321-6.
  57. Gilliam AD, Broome P, Topuzov EG, Garin AM, Pulay I, Humphreys J, et al. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas. 2012 Apr;41(3):374-9. DOI: 10.1097/MPA.0b013e31822ade7e.
  58. Tsang KY, Palena C, Gulley J, Arlen P, Schlom J. A human cytotoxic T-lymphocyte epitope and its agonist epitope from the nonvariable number of tandem repeat sequence of MUC-1. Clin Cancer Res. 2004 Mar 15;10(6):2139-49.
  59. Finn OJ, Jerome KR, Henderson RA, Pecher G, Domenech N, Magarian-Blander J, et al. MUC-1 epithelial tumor mucin-based immunity and cancer vaccines. Immunol Rev. 1995 Jun;145:61-89.
  60. Kaufman HL, Kim-Schulze S, Manson K, DeRaffele G, Mitcham J, Seo KS, et al. Poxvirus-based vaccine therapy for patients with advanced pancreatic cancer. J Transl Med. 2007;5:60. DOI: 10.1186/1479-5876-5-60.
  61. Galili U. The alpha-gal epitope and the anti-Gal antibody in xenotransplantation and in cancer immunotherapy. Immunol Cell Biol. 2005 Dec;83(6):674-86. DOI: 10.1111/j.1440-1711.2005.01366.x.
  62. Springett GM. Novel pancreatic cancer vaccines could unleash the army within. Cancer Control. 2014 Jul;21(3):242-6.
  63. Hardacre JM, Mulcahy M, Small W, Talamonti M, Obel J, Krishnamurthi S, et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. J Gastrointest Surg. 2013 Jan;17(1):94-100; discussion p -1. DOI: 10.1007/s11605-012-2064-6.
  64. Gunderson AJ, Kaneda MM, Tsujikawa T, Nguyen AV, Affara NI, Ruffell B, et al. Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer. Cancer Discov. 2016 Mar;6(3):270-85. DOI: 10.1158/2159-8290.CD-15-0827.
  65. Masso-Valles D, Jauset T, Serrano E, Sodir NM, Pedersen K, Affara NI, et al. Ibrutinib exerts potent antifibrotic and antitumor activities in mouse models of pancreatic adenocarcinoma. Cancer Res. 2015 Apr 15;75(8):1675-81. DOI: 10.1158/0008-5472.CAN-14-2852.
  66. Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular switches. Cell Signal. 2010 Aug;22(8):1175-84. DOI: 10.1016/j.cellsig.2010.03.001.
  67. Khan WN. Regulation of B lymphocyte development and activation by Bruton’s tyrosine kinase. Immunol Res. 2001;23(2-3):147-56. DOI: 10.1385/IR:23:2-3:147.
  68. Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, Aints A, et al. Bruton’s tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev. 2009 Mar;228(1):58-73. DOI: 10.1111/j.1600-065X.2008.00741.x.
  69. de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012 Mar 15;119(11):2590-4. DOI: 10.1182/blood-2011-11-390989.
  70. Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012 Feb 2;119(5):1182-9. DOI: 10.1182/blood-2011-10-386417.
  71. Soucek L, Buggy JJ, Kortlever R, Adimoolam S, Monclus HA, Allende MT, et al. Modeling pharmacological inhibition of mast cell degranulation as a therapy for insulinoma. Neoplasia. 2011 Nov;13(11):1093-100.
  72. Herman SE, Sun X, McAuley EM, Hsieh MM, Pittaluga S, Raffeld M, et al. Modeling tumor-host interactions of chronic lymphocytic leukemia in xenografted mice to study tumor biology and evaluate targeted therapy. Leukemia. 2013 Dec;27(12):2311-21. DOI: 10.1038/leu.2013.131.
  73. Schaeffer EM, Debnath J, Yap G, McVicar D, Liao XC, Littman DR, et al. Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity. Science. 1999 Apr 23;284(5414):638-41.
  74. Takeba Y, Nagafuchi H, Takeno M, Kashiwakura J, Suzuki N. Txk, a member of nonreceptor tyrosine kinase of Tec family, acts as a Th1 cell-specific transcription factor and regulates IFN-gamma gene transcription. J Immunol. 2002 Mar 1;168(5):2365-70.
  75. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013 Oct 10;122(15):2539-49. DOI: 10.1182/blood-2013-06-507947.
  76. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013 Apr;13(4):227-42. DOI: 10.1038/nri3405.
  77. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015 Apr 13;27(4):450-61. DOI: 10.1016/j.ccell.2015.03.001.
  78. Gross JA, St John T, Allison JP. The murine homologue of the T lymphocyte antigen CD28. Molecular cloning and cell surface expression. J Immunol. 1990 Apr 15;144(8):3201-10.
  79. Azuma M, Ito D, Yagita H, Okumura K, Phillips JH, Lanier LL, et al. B70 antigen is a second ligand for CTLA-4 and CD28. Nature. 1993 Nov 4;366(6450):76-9. DOI: 10.1038/366076a0.
  80. Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014 Dec 4;371(23):2189-99. DOI: 10.1056/NEJMoa1406498.
  81. Littman DR. Releasing the Brakes on Cancer Immunotherapy. Cell. 2015 Sep 10;162(6):1186-90. DOI: 10.1016/j.cell.2015.08.038.
  82. Aglietta M, Barone C, Sawyer MB, Moore MJ, Miller WH, Jr., Bagala C, et al. A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. Ann Oncol. 2014 Sep;25(9):1750-5. DOI: 10.1093/annonc/mdu205.
  83. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010 Oct;33(8):828-33. DOI: 10.1097/CJI.0b013e3181eec14c.
  84. Jacob JA. Cancer Immunotherapy Researchers Focus on Refining Checkpoint Blockade Therapies. JAMA. 2015 Nov 24;314(20):2117-9. DOI: 10.1001/jama.2015.10795.
  85. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012 Jun 28;366(26):2443-54. DOI: 10.1056/NEJMoa1200690.
  86. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010 Jul 1;28(19):3167-75. DOI: 10.1200/JCO.2009.26.7609.
  87. Witkiewicz A, Williams TK, Cozzitorto J, Durkan B, Showalter SL, Yeo CJ, et al. Expression of indoleamine 2,3-dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. J Am Coll Surg. 2008 May;206(5):849-54; discussion 54-6. DOI: 10.1016/j.jamcollsurg.2007.12.014.
  88. Yeung AW, Terentis AC, King NJ, Thomas SR. Role of indoleamine 2,3-dioxygenase in health and disease. Clin Sci (Lond). 2015 Oct;129(7):601-72. DOI: 10.1042/CS20140392.
  89. Johnston FM, Tan MC, Tan BR, Jr., Porembka MR, Brunt EM, Linehan DC, et al. Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer. Clin Cancer Res. 2009 Nov 1;15(21):6511-8. DOI: 10.1158/1078-0432.CCR-09-0565.
  90. Hassan R, Ebel W, Routhier EL, Patel R, Kline JB, Zhang J, et al. Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin. Cancer Immun. 2007;7:20.
  91. Jeanbart L, Swartz MA. Engineering opportunities in cancer immunotherapy. Proc Natl Acad Sci U S A. 2015 Nov 24;112(47):14467-72. DOI: 10.1073/pnas.1508516112.
  92. Palucka K, Banchereau J. SnapShot: cancer vaccines. Cell. 2014 Apr 10;157(2):516- e1. DOI: 10.1016/j.cell.2014.03.044.
  93. Coffelt SB, de Visser KE. Revving Up Dendritic Cells while Braking PD-L1 to Jump-Start the Cancer-Immunity Cycle Motor. Immunity. 2016 Apr 19;44(4):722-4. DOI: 10.1016/j.immuni.2016.03.014.
  94. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012 Apr 27;149(3):656-70. DOI: 10.1016/j.cell.2012.01.058.
  95. Gjertsen MK, Bakka A, Breivik J, Saeterdal I, Solheim BG, Soreide O, et al. Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet. 1995 Nov 25;346(8987):1399-400.
  96. Gjertsen MK, Buanes T, Rosseland AR, Bakka A, Gladhaug I, Soreide O, et al. Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma. Int J Cancer. 2001 May 1;92(3):441-50.
  97. Weden S, Klemp M, Gladhaug IP, Moller M, Eriksen JA, Gaudernack G, et al. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer. 2011 Mar 1;128(5):1120-8. DOI: 10.1002/ijc.25449.
  98. Infante JR, Jones SF, Bendell JC, Spigel DR, Yardley DA, Weekes CD, et al. A phase I, dose-escalation study of pomalidomide (CC-4047) in combination with gemcitabine in metastatic pancreas cancer. Eur J Cancer. 2011 Jan;47(2):199-205. DOI: 10.1016/j.ejca.2010.09.002.
  99. Burris HA, 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-13.
  100. Amedei A, Niccolai E, Prisco D. Pancreatic cancer: role of the immune system in cancer progression and vaccine-based immunotherapy. Hum Vaccin Immunother. 2014;10(11):3354-68. DOI: 10.4161/hv.34392.
  101. Takahara A, Koido S, Ito M, Nagasaki E, Sagawa Y, Iwamoto T, et al. Gemcitabine enhances Wilms’ tumor gene WT1 expression and sensitizes human pancreatic cancer cells with WT1-specific T-cell-mediated antitumor immune response. Cancer Immunol Immunother. 2011 Sep;60(9):1289-97. DOI: 10.1007/s00262-011-1033-3.
  102. Nowak AK, Robinson BW, Lake RA. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res. 2003 Aug 1;63(15):4490-6.
  103. Liu X, Pu Y, Cron K, Deng L, Kline J, Frazier WA, et al. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat Med. 2015 Oct;21(10):1209-15. DOI: 10.1038/nm.3931.
  104. Marabelle A, Filatenkov A, Sagiv-Barfi I, Kohrt H. Radiotherapy and toll-like receptor agonists. Semin Radiat Oncol. 2015 Jan;25(1):34-9. DOI: 10.1016/j.semradonc.2014.07.006.
  105. Eriksson D, Stigbrand T. Radiation-induced cell death mechanisms. Tumour Biol. 2010 Aug;31(4):363-72. DOI: 10.1007/s13277-010-0042-8.
  106. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):862-70. DOI: 10.1016/j.ijrobp.2003.09.012.
  107. Reynders K, De Ruysscher D. Radiotherapy and Immunotherapy: Improving Cancer Treatment through Synergy. Prog Tumor Res. 2015;42:67-78. DOI: 10.1159/000437185.
  108. Teng F, Kong L, Meng X, Yang J, Yu J. Radiotherapy combined with immune checkpoint blockade immunotherapy: Achievements and challenges. Cancer Lett. 2015 Aug 28;365(1):23-9. DOI: 10.1016/j.canlet.2015.05.012.
  109. Twyman-Saint Victor C, Rech AJ, Maity A, Rengan R, Pauken KE, Stelekati E, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015 Apr 16;520(7547):373-7. DOI: 10.1038/nature14292.
  110. Sahlin M, Bauden MP, Andersson R, Ansari D. Radioimmunotherapy–a potential novel tool for pancreatic cancer therapy? Tumour Biol. 2015 Jun;36(6):4053-62. DOI: 10.1007/s13277-015-3479-y.
  111. Ngiow SF, McArthur GA, Smyth MJ. Radiotherapy complements immune checkpoint blockade. Cancer Cell. 2015 Apr 13;27(4):437-8. DOI: 10.1016/j.ccell.2015.03.015.

 

 

 

 

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