Among all cancers, pancreatic cancer stands apart. Everything about the disease makes it hard to diagnose and treat. It often exhibits few symptoms before the cancer has reached late stages. While there are known risk factors, such as smoking, obesity, and some tendency for the cancer to run in families, many who receive the diagnosis have no known risks. So far, there are no biomarkers available that could allow widespread screening of the disease.1
Once pancreatic cancer is found, the location of the pancreas itself makes removing the tumor difficult and for most patients, impossible. And then there is the challenge of treatment. In pancreatic ductal adenocarcinoma (PDAC), which accounts for 90% of all cases, tumors are notoriously resistant to chemotherapy; they are characterized by dense stroma with few blood vessels, inhibiting drug delivery.
Taken together, these hurdles leave grim statistics. Estimates from the American Cancer Society put the number of new cases in the United States at 46,420 for 2014, with 39,590 deaths.2 While pancreatic cancer accounts for only 3% of all cancer cases, it causes 7% of all cancer deaths,2 making it the fourth-leading cause of cancer death in the country. With a 5-year survival rate of 6%, the disease is “the only one of the top 10 cancer killers with a 5-year survival rate still in the single digits,” according to the Pancreatic Cancer Action Network (PanCAN).3
Pancreatic cancer’s share in the cancer death toll in the United States has been slowly rising, not only because of improved treatments for other cancers, but also because rising rates of obesity and diabetes appear to be contributing to more cases, according to epidemiologist Ahmedin Jemal, DVM, PhD, vice president for surveillance and health services research for the American Cancer Society.4 PanCAN estimates that the number of new cases will grow 55% between 2010 and 2030, and that pancreatic cancer could become the second-leading cause of cancer death in the United States.3
And yet, there is hope.
Clinical trials across the country are investigating multiple forms of immunotherapy to treat PDAC, often in combinations or in sequence with newer, more powerful forms of chemotherapy.5 In some cases, researchers are borrowing lessons learned from the successful use of immunotherapy to treat metastatic melanoma
with ipilimumab or castration-resistant prostate cancer with sipuleucel-T.6 Researchers say they are learning as much from their successes as their failures, and while critical phase 3 trials remain, there are signs that longer, better survival may be on the horizon.6,7
What Researchers Are Learning
For some time, researchers have understood that KRAS is a driver of PDAC progression.7,8 According to the National Cancer Institute (NCI), KRAS is mutated in approximately 95% of all cases of PDAC, the highest percentage of all solid malignancies.1,8 Translating that knowledge into effective treatment has proved exceedingly
difficult, as described by Marina Pasca diMagliano, PhD, and Craig D. Logsdon, PhD, in their 2013 review for Gastroenterology: “Early attempts to use this molecule as a specific biomarker of the disease, or inhibit its activity as a cancer therapy, failed. This left a situation in which everyone was aware of the association between this important oncogene and pancreatic cancer, but no one knew what to do about it.”7
DiMagliano and Logsdon and others report that many assumptions about KRAS and its role in PDAC have been set aside, aided by the use of mouse models, genome
sequencing projects, and further exploration into the unique environment of the pancreatic tumor itself. For example, a review this spring in the British Journal of Cancer outlines how recent efforts bypass attempts to target KRAS directly and instead direct attention to its signaling networks or downstream effector pathways.9
Much important work involves understanding the qualities of the collagen-rich fibrosis around the tumor, which not only acts as a barrier to therapy, but may also be the body’s way of containing cancer cells, according to Hiyadatullah G. Munshi, MD, associate professor of medicine in the Department of Medicine, Division of Hematology/Oncology at Northwestern University Feinberg School of Medicine, in an e-mail to Evidence-Based Oncology.
Throughout, clinical trials are informed by an important lesson: when fighting pancreatic cancer, the battle isn’t just against the tumor; it’s against the tumor in a setting hardwired to resist treatment. This makes the central premise of immunotherapy—to train the body to use its own immune system to battle cancer— even more challenging than usual.1,6,7,10
Whole Cell Vaccines
As Jennifer N. Uram, PhD, and Dung T. Le, MD, explain in Current Problems in Cancer, treating a difficult disease like pancreatic cancer with whole cell vaccines delivers multiple antigens, avoiding “the difficulty of picking the optimal tumor antigen to target.”6 Two such vaccines advancing in clinical trials are algenpentucel-L and GVAX, an acronym for granulocytemacrophage colony-stimulating factor (GM-CSF) gene-transfected tumor cell vaccine.11 GVAX is made from irradiated pancreatic cell lines that secrete GM-CSF.12
Algenpentucel-L, which is being developed by NewLink Genetics, follows years of work to understand the responses to alpha-gal, a carbohydrate to which humans have a preexisting immunity.13 Experiments with mice more than a decade ago yielded the theory that using alphagal to trigger an immune response could provide a protective, immune response to cancer.14 The vaccine uses alpha-gal—modified human cancer cells, which are designed to jump-start the immune system. In effect, when the body attacks the vaccine, the battle against the cancer escalates, too.
The vaccine has been studied in combination with gemcitabine, long the standard chemotherapy for PDAC, in patients with resected cancer. Phase 2 results reported by Hardacre, et al, involved 70 patients who were treated with gemcitabine and 5—fluorouracil-based chemoradiotherapy, as well as algenpantucel-L. The average number of doses was 12, over approximately 8 months. After a median follow-up of 21 months, the 12-month disease-free survival (DFS) was 62%, and the 12-month overall survival (OS) was 86%. The most common adverse events were injection site pain and induration.14 Reports on the phase 2 trial noted the longer than normal DFS, as well as the presence of antibodies in affected patients that could someday guide future treatment.6
A phase 3 trial involving 772 patients, randomized to receive either standard chemotherapy or chemotherapy plus algenpantucel-L, completed enrollment in September 2013 and is ongoing.12,15 A separate phase 3 trial for patients with locally advanced cancer, randomized to receive chemotherapy or chemotherapy plus algenpantucel-L, is currently enrolling.16
GVAX has been studied as a monotherapy, but its most promising results have involved its use in combination therapy. Work on this vaccine stems from the many efforts to target KRAS directly, and the realization that a different approach was needed. In 2012, researchers found that the KRAS mutation triggers expression of GM-CSF, and that when the molecule comes from tumors it converts immature immune cells into suppressive immune cells. Finding a way to block this activity would allow the immune system to fight the tumor, and it could halt tumor progression.17
In July 2014, the FDA granted breakthrough status to a combination of GVAX and CRS-207, a live-attenuated Listeria monocytogenes (Lm), modified to express the protein mesothelin and made safe for human use.6,12,18 Le and her colleagues from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins had presented results with the combination immunotherapy at the February 2014 Gastrointestinal Cancers Symposium of the American Society of Clinical Oncology, where Le said, “This is the first time a randomized study has shown that immunotherapy is effective in pancreatic cancer.”18
The study involved 90 PDAC patients; all had received some treatment for metastatic disease: 83% had 1 prior treatment and 51% had 2 or more treatments. They were randomized to receive 2 doses of GVAX followed by 4 doses of CRS-207, or 6 doses of GVAX alone, every 3 weeks. (All patients received low-dose cyclophosphamide before GVAX.) Courses could be repeated.
At a median follow-up of 7.8 months, among patients who received at least 1 dose of the vaccine, median OS was 6.1 months for the combination compared with 3.9 months for GVAX alone—a 41% reduction in risk. The greatest reduction in risk was among patients who had all 3 doses, including at least 2 GVAX doses and 1 CRS-207 dose. For this group, median OS was 9.7 months, compared with 4.6 months for GVAX alone, a 47% reduction in risk. Differences were observed in the subgroup of patients who had 2 or more prior chemotherapy regimens. For this group, the combination immunotherapy resulted in a median OS of 5.7 months compared with 3.7 months with GVAX, a 70% reduction. In the group that received at least 3 doses, median OS was 8.3 months compared with 4 months, a 68% reduction in risk.17 Grade 3/4 side effects were lymphopenia (8.2%), pyrexia (4.9%), fatigue (4.9%), and aspartate aminotransferase increase (4.9%). Local reactions were reported at the administration
site for GVAX.12
Ipilimumab, in Sequence and in Combinations
As seen elsewhere, trials involving ipilimumab are revealing the value of combination therapy and sequencing immunotherapy after a course of chemotherapy, which can stabilize PDAC and give immunotherapy a better chance of success.5 Developments in immunotherapy for pancreatic cancer have been complemented in recent years by new weapons in chemotherapy:
• FOLFIRINOX is a combination of 4 drugs: folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin. A 2011 study in the New England Journal of Medicine reported a median OS of 11.1 months for patients with metastatic cancer taking this combination, compared with 6.8 months with gemcitabine, but noted strong toxicity.19
• Abraxane (nab-paclitaxel) was approved by the FDA in September 2013 to be used with gemcitabine for metastatic pancreatic cancer, after trials showed OS improved by 1.8 months with fewer side effects than occurred with FOLFIRINOX. The chemotherapy combination was shown to delay tumor growth as well, according to the FDA.20
Why ipilimumab for pancreatic cancer? Its blockade of the CTLA-4 inhibitory signal was found effective in depleting regulatory T cells, which suppress anti-tumor immune response in PDAC. A phase 2 trial with ipilimumab as monotherapy (3 mg/kg) did not produce a clinical response. However, 1 patient’s brief delayed response to a tumor marker test indicated a small immune response, and suggested that stronger doses or a combination strategy might prove effective.6
To test this, Le’s group at Johns Hopkins randomized 30 patients with previously treated PDAC in 2 arms. Results were reported in September 2013 in the Journal of Immunotherapy. The first arm received ipilimumab alone, but at a higher dose than in the previous study (10 mg/kg); the second arm received ipilimumab (10 mg/kg) plus GVAX. Doses were administered every 3 weeks for 4 total doses, followed by maintenance doses every 12 weeks. In the first arm, 2 patients showed stable disease, but that result was not borne out in CA19-9 testing, which evaluates tumorassociated antigens. In the second arm, 3 patients had evidence of prolonged stabilization—at 31, 71, and 81 weeks—and 7 patients showed declines in CA19-9 testing. Median OS, 3.6 months compared with 5.7 months, and 1-year OS, 7% compared with 27%, favored the second arm.21
Multiple clinical trials involving ipilimumab are now recruiting patients or are under way. Hopkins’ Kimmel Comprehensive Center is enrolling patients in another phase 2 trial; patients will be treated first with FOLFINIROX and then with ipilimumab and GVAX. A phase 3 study at Northwestern University will evaluate ipilimumab with gemcitabine in late-stage or recurrent unresectable pancreatic cancer. Pancreatic cancer patients will be included in a broader study evaluating the effectiveness of another combination, ipilimumab and nivolumab, which will enroll patients with different types of cancer.22
In his e-mail, Northwestern’s Munshi said that much work remains before ipilimumab can be approved for widespread use to treat pancreatic cancer, and he doubts it will be approved as a single agent. “In combination with chemotherapy, one has to be careful that there are no untoward toxicities,” he said. Approval in combination with a vaccine is a possibility, however.
PANVAC: Injecting the Tumor Directly
The June 2014 American Association of Cancer Research meeting on pancreatic cancer, held in New Orleans, included results from Rutgers Cancer Institute of New Jersey (CINJ) on a phase 1 trial involving PANVAC. This vaccine comes in varieties derived from smallpox and Fowlpox, which are treated with gene additives to stimulate the immune system to attack pancreatic cancer. Edmund Lattime, PhD, CINJ associate director for education and training, and Elizabeth Poplin, MD, co-director of the Cancer Institute’s Gastrointestinal/Hepatobiliary Program, and a professor of medicine at Robert Wood Johnson Medical School, were lead investigators.23
There were 2 phases to the trial. In the first phase, researchers directly injected a live form of the Fowlpox vaccine, which cannot multiply, into tumors for patients who were not candidates for surgery, seeking to shrink tumors without allowing fragments to spread elsewhere. Then patients received a booster, a live but weakened form of smallpox vaccine that can still multiply, injected into the arm. In the second phase, patients received a higher dose of the Fowlpox-derived vaccine into the tumor.23
Twelve patients began the trial; 2 had rapid progression and were removed, while the remaining 10 received gemcitabine. Three were found to have distant metastatic disease, with OS ranging from 6 to 22 months. The other 7 patients had OS ranging from 4 to 36 months, and none developed disease that spread beyond the original tumor.
“While the median survival rate for patients without distant metastasis was nearly a year-and-a-half with this treatment, there was 1 patient whose disease remained clinically stable for nearly 3 years,” the researchers said in a statement from CINJ. “When you have a disease that only carries a 5-year, 6% survival rate, these findings are very encouraging.”23
Much has happened since Gunturu et al asked, “Are we there yet?” in a January 2013 review article on immunotherapy in pancreatic cancer.10 The February 2014 report from NCI, “Scientific Framework for Pancreatic Ductal Adenocarcinoma,” a call to action required by the Recalcitrant Cancer Research Act of 2012,1 suggests that while the quest to find effective treatment for pancreatic cancer is no less challenging, a road map is at last emerging.References
1. A scientific framework for pancreatic ductal adenocarcinoma. National Cancer Institute. http://www.cancer.gov/cancertopics/types/pancreatic. Published February 2014. Accessed August 19, 2014.
2. Pancreatic cancer, key statistics. American Cancer Society website. http://www.cancer.org/cancer/pancreaticcancer/detailedguide/pancreatic-cancer-key-statistics. Updated June 11, 2014. Accessed September 3, 2014.
3. Pancreatic Cancer Action Network website. http://www.pancan.org/advocate/advocacyaction-center-18/. Accessed September 3, 2014.
4. Pancreatic deaths creep up. Cancer Discovery. 2013;3:OF3. http://cancerdiscovery.aacrjournals.org/content/3/3/OF3.full. Published January 31, 2013. Accessed September 9, 2014.
5. Fifty two results listed for pancreatic cancer trials with immunotherapy. Clinicaltrials.gov. Accessed September 7, 2014.
6. Uram JN, Le DT. Current advances in immunotherapy for pancreatic cancer. Curr Probl Cancer. 2013;37(5):273-279.
7. DiMagliano MP, Logsdon CD. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology. 2013;144(6):1220-1229.
8. National Cancer Institute. Pancreatic cancer: an agenda for action. Report of the Pancreatic Cancer Progress Review Group. NIH Publication No. 01-4940. Bethesda, MD: NCI; 2001. http://planning.cancer.gov/library/2001pancreatic.pdf. Accessed September 6, 2014.
9. Eser S, Schneike A, Schneider G, Saur D. Oncogenic KRAS signaling in pancreatic cancer. BJC. 2014;111:817-822.
10. Gunturu KS, Rossi GR, Saif MW. Immunotherapy updates in pancreatic cancer: are we there yet? Ther Adv Med Oncol. 2013;5(1):81-88.
11. Vaccines in cancer: GVAX, a GM-CSF gene vaccine. Informa Healthcare website. http://informahealthcare.com/doi/abs/10.1586/147605184.108.40.2069. Published June 2005. Accessed September 3, 2014.
12. Inman S. Immunotherapy combination receives breakthrough designation for pancreatic cancer. OncLive website. http://www.onclive.com/ web-exclusives/Immunotherapy-Combination-Receives-Breakthrough-Designation-for-Pancreatic-Cancer#sthash.kZupwedh.dpuf. Published July 21, 2014. Accessed September 6, 2014.
13. NewLink Genetics completes patient enrollment in phase 3 algenpentucel-L (IMPRESS) clinical study [press release]. http://investors.linkp.com/ releasedetail.cfm?ReleaseID=791024. Ames, IA: Newlink Genetics; September 13, 2013.
14. Unfer RC, Hellrung D, Link CJ Jr. Immunity to the alpha (1,3) galactosyl epitope provides protection in mice challenged with colon cancer cells expressing alpha (1,3) galactosyl-transferase: a novel suicide gene for cancer gene therapy. Cancer Res. 2003;63(5):987-993.
15. Hardacre JM, Mulcahy M, Small W. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. Gastrointrest Surg. 2013;17(1):94-100.
16. PILLAR study. NewLink Genetics website. http://www.newlinkgenetics.com/pillar-study. Accessed September 6, 2014.
17. Pancreatic cancer. Cancer Research Institute website. http://www.cancerresearch.org/cancerimmunotherapy/impacting-all-cancers/pancreaticcancer#sthash.Q6kERZBa.dpuf. Accessed September 3, 2014.
18. Helwick C. Immunotherapy duo improves survival in metastatic pancreatic cancer. ASCO Post. http://www.ascopost.com/issues/february-15,-2014/immunotherapy-duo-improvessurvival-in-metastatic-pancreatic-cancer.aspx. Published February 15, 2014. Accessed September 3, 2014.
19. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-1825.
20. FDA approves Abraxane for late-stage pancreatic cancer [press release]. Silver Spring, MD: FDA Newsroom; September 6, 2013. http://www.fda.gov/newsevents/newsroom/
21. Le DT, Lutz E, Uram JN, 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;36(7):382-389.
22. Clinicaltrials.gov. Six results listed for pancreatic cancer trials with ipilimumab. Accessed September 6, 2014.
23. Encouraging period of stable disease suggested in direct injection vaccine treatment of pancreatic cancer [press release]. New Brunswick, NJ: Cancer Institute of New Jersey; May 20, 2014. http://www.cinj.org/encouraging-stable-disease-suggesteddirect-injection-vaccine-treatment-pancreaticcancer.