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Ability to harness immune system may provide urgently needed therapies for pancreatic cancer
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In contrast to the steady increase in survival for most cancers, advances have been slow for pancreatic cancers.
Five-year relative survival is less than 10%. Due to inadequate screening methods, more than half of all pancreatic cancer cases are diagnosed at distant stage, for which the 5-year survival is close to 2%.
There are limited targeted therapy options for the treatment of pancreatic cancer; however, researchers have identified mechanisms to harness the body’s immune system to combat this lethal disease.
Investigators also have characterized molecular subtypes of pancreatic cancer, which may allow for the development of novel targeted therapies.
Progress in immunotherapy
Hailed as one of the biggest breakthroughs in modern cancer medicine, immunotherapy takes advantage of receptors (eg, CTLA-4 and PD-1/PD-L1) located on cancer cells and T cells to take the brakes off the immune system. This inevitably results in T-cell infiltration of the tumor and cell apoptosis.
Based on the success observed in melanoma and non–small cell lung cancer, researchers are studying ways to apply immunotherapy to pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) exists in a complex desmoplastic stroma, which provides a structural framework for tumor growth but also masks the tumor from immune surveillance.
For many years, PDAC has been considered a nonimmunogenic cancer, partly due to this barrier within the tumor microenvironment. As such, therapeutic approaches focusing on overcoming T-cell immunologic checkpoints are not necessarily expected to be effective in pancreatic cancer.
One mechanism to overcome this barrier involves targeting CD40 expressed on the cell surface of immune cells. CD40 activates T cells by directly binding to CD154 on the T-cell surface. Anti-CD40 agonist antibodies induce tumor regression via stimulation of T-cell activation and macrophage reprogramming.
The addition of anti-CD40 agonist antibody to gemcitabine in chemotherapy-naive patients with surgically incurable PDAC improved PFS from 5.7 months to 7.4 months. Ongoing studies are evaluating anti-CD40 agonist antibody with or without gemcitabine plus nab-paclitaxel to further improve efficacy.
CTLA-4, a costimulatory molecule expressed on activated T cells, has been an attractive immune target for many years. By releasing the “brake” on T-cell activation, CTLA-4 blockade enhances long-lasting immunogenicity.
Ipilimumab (Yervoy, Bristol-Myers Squibb), an anti–CTLA-4 immunoglobulin G1 antibody used in the treatment of metastatic melanoma, and tremelimumab (AstraZeneca) also are being tested in PDAC.
A phase 2 trial of ipilimumab monotherapy for locally advanced or metastatic PDAC yielded no responders, and researchers concluded single-agent anti–CTLA-4 was ineffective; however, ongoing trials are investigating anti–CTLA-4 antibody in combination with gemcitabine or FOLFIRINOX.
A randomized phase 2 trial evaluated ipilimumab in combination with a granulocyte-macrophage colony–stimulating factor cell-based vaccine (GVAX Pancreas, Aduro Biotech) in patients with previously treated PDAC. Results showed a modest improvement in median OS (see Table; HR = 0.51) and 1-year OS (27% vs. 7%) in the combination arm. These data suggest the combination of anti–CTLA-4 antibody and a targeted vaccine may improve efficacy.
PD-1, an inhibitory receptor that down-regulates T-cell activation when bound to PD-L1 or PD-L2 on tumor cells, has been shown to be a promising target for immunotherapies, evidenced by approvals in melanoma, lung cancer, renal cell carcinoma, lymphoma, head/neck cancer and urothelial carcinomas. In light of these promising results, anti–PD-1/PD-L1 agents are being evaluated in numerous pancreatic cancer clinical trials, in monotherapy and combination regimens.
Investigators also are exploring how and why pancreatic cancer evades immune surveillance. For example, cancer-associated fibroblasts and production of chemokine ligand 12 (CXCL12) have been shown to play a key role in local immunosuppression, preventing T-cell infiltration of the tumor. Depletion of cancer-associated fibroblasts or inhibition of CXCL12 may sensitize pancreatic cells to the antitumor effects of both anti–CTLA-4 and anti–PD-1 antibodies, and they are being studied in clinical trials.
Vaccines
Cancer vaccines are biological preparations that involve administering an antigen that is specific for a particular tumor type and boosts the body’s natural ability to attack the cancer.
Algenpantucel-L (NewLink Genetics) is an irradiated, live combination of two human allogeneic PDAC cell lines transfected to express murine alpha 1,3-galactosyltransferase. Vaccination is associated with expression of murine alpha 1,3-galactosyl carbohydrate residues on cell membrane glycoproteins of the vaccine pancreatic cell allograft. Murine epitopes not present on human cells then induce a hyperacute rejection of the vaccine allografts, resulting in rapid activation of antibody-dependent cell-mediated cytotoxicity toward the allograft cells and endogenous PDAC cells.
A phase 2 study of 70 patients who underwent R0 or R1 resection who received algenpantucel-L combined with adjuvant gemcitabine and 5-FU–based chemoradiotherapy resulted in a 1-year DFS of 62% — compared with 50% in historical controls — and 1-year OS of 86%, compared with 69% in historical controls.
However, the phase 3 IMPRESS study of gemcitabine plus chemoradiotherapy with or without algenpantucel-L in patients with resected PDAC showed no statistically significant improvement in OS (median, 27.3 months vs. 30.4 months) and no difference in long-term survival. Ongoing studies are evaluating algenpantucel-L in combination with more commonly used chemotherapy regimens, such as gemcitabine/nab-paclitaxel or FOLFIRINOX, and the impact of immunological biomarkers.
GVAX and CRS-207 (Aduro Biotech) are cancer vaccines that have been evaluated in PDAC.
GVAX is composed of two irradiated, GM-CSF–secreting allogeneic PDAC cell lines administered 24 hours after treatment with low-dose cyclophosphamide to inhibit regulatory T cells. GVAX induces T cells against a broad array of PDAC antigens, including mesothelin-specific T cells.
A phase 2 trial of 60 patients with resected PDAC investigated the efficacy of GVAX after 5-FU–based chemoradiation. Median DFS was 17.3 months and median OS was 24.8 months. Post-immunotherapy induction of mesothelin-specific CD8-positive T cells also correlated with DFS.
CRS-207 is a recombinant live-attenuated, double-deleted Listeria monocytogene, engineered to secrete mesothelin into the cytosol of infected antigen-presenting cells, which ultimately gets presented in the context of major histocompatibility complex molecules.
A randomized study of 90 patients with previously treated PDAC evaluated cyclophosphamide/GVAX followed by four doses of CRS-207 vs. six doses of cyclophosphamide/GVAX alone. Results showed a modest improvement in median OS (see Table; P = .02). Further, enhanced mesothelin-specific CD8-positive T-cell responses were associated with longer OS, regardless of treatment arm.
Surprisingly, the follow-up phase 3 trial demonstrated median OS of 3.8 months among those who received CRS-207 and GVAX; 5.4 months among those who received CRS-207 alone; and 4.6 months among those who received chemotherapy. These results suggested CRS-207 monotherapy may have more activity than originally presumed.
IMM-101 (Immodulon Therapeutics) is a systemic immune modulator that contains heat-killed Mycobacterium obuense. IMM-101 acts on cells of the innate immune system (eg, antigen-presenting cells) by interacting with and activating various immune receptors, resulting in a cytotoxic effect against tumors.
A randomized phase 2 study included 110 patients with treatment-naive locally advanced or metastatic PDAC. Researchers assigned patients to IMM-101 plus gemcitabine or gemcitabine alone. Patients assigned the combination achieved longer median OS (see Table) but the difference was not statistically significant. Among those with metastatic disease, median OS significantly improved among those in the combination group (7 months vs. 4.4 months; P < .05).
Focus on trials
Despite the development of immunotherapies and vaccines, the prognosis of patients with advanced pancreatic cancer remains dismal. Thus, availability and enrollment onto clinical trials is critical.
Numerous tumor-associated antigens have been identified in PDAC, including mesothelin, mucin 1 (MUC1), and KRAS. Antibodies to these antigens appear in the serum of patients with PDAC and may correlate with survival. Further, the accumulation of CD8-positive T cells correlates with improved survival.
Other immunotherapy-related agents being evaluated in clinical trials include telomerase peptide vaccines, surviving DNA vaccines, antigen-pulsed dendritic cells and heat shock protein–peptide complex.
Immunotherapy has the potential to treat minimal residual disease after pancreatic resection and provides a less toxic option than standard chemotherapy.
According to clinicaltrials.gov, there are more than 80 studies investigating the use of immunotherapy to combat PDAC. There is an urgent need to prolong survival for patients with PDAC, and enrollment onto clinical trials should be strongly considered.
Integrated genomic analysis of 456 PDACs identified 32 recurrently mutated genes that aggregate into 10 pathways, and expression analysis defined four subtypes: squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine. These findings infer differences in molecular evolution, providing additional opportunities for targeted therapeutic development.
As more biological targets and mechanisms are being discovered, additional evaluation of how to enhance the efficacy of immunotherapies and augment the immune-elicited responses is required, including checkpoint inhibition and more complex combination trial designs.
Due to the complex tumor microenvironment of pancreatic cancer, it is unlikely that single-agent immunotherapies or vaccines will be very effective. Novel approaches are required to optimize the effect of immunotherapy in pancreatic cancer, such as dismantling the stroma, targeting multiple checkpoints and reducing the level of fibrosis present in the microenvironment.
Although the magnitude of benefit may not compare to that noted in melanoma, harnessing these novel mechanisms in immunotherapy may provide urgent therapeutic options for patients who suffer from this lethal disease, for which limited targeted therapy options exist.
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For more information:
Jai N. Patel, PharmD, is chief of pharmacology research and phase 1 trials at Levine Cancer Institute at Carolinas HealthCare System, as well as adjunct assistant professor at UNC Eshelman School of Pharmacy. He also is a HemOnc Today Editorial Board member. He can be reached at jai.patel@carolinashealthcare.org.
Disclosure: Patel reports no relevant financial disclosures.