Cancer Immunotherapy

Pancreatic Cancer

Pancreatic cancer is the most lethal cancer, and new therapies are urgently needed to impact pancreatic cancer treatment and to extend and save pancreatic cancer patients’ lives. Immune-based strategies to detect and treat pancreatic cancer during the early stages of development, as well as new immunological approaches to treat advanced disease, are showing significant promise where other approaches have failed. This page features information on pancreatic cancer and immunotherapy clinical trials for pancreatic cancer patients, and highlights the Cancer Research Institute’s role in working to bring effective immune-based cancer treatments to pancreatic cancer patients.

Pancreatic cancer is the fourth-leading cause of cancer-related death in the United States, with a 5-year survival rate of less than 6%. Compared to other cancers, it shows marked resistance to conventional forms of chemotherapy, and there are limited capabilities to diagnose and treat the disease in its earliest stages. No current treatment option has demonstrated long-term benefit in patients with advanced disease who are not eligible for surgery—which represents the majority (80%) of pancreatic cancer cases. Immune-based strategies to detect and treat pancreatic cancer during the early stages of development, as well as new immunological approaches to treat advanced disease, are showing significant promise where other approaches have failed.


Brief Statistics

Urgent Need: Pancreatic ductal adenocarcinoma (PDA), which accounts for more than 90% of pancreatic cancer cases, is highly lethal; for all stages combined, the 1-and 5-year relative survival rates are 26% and 6%, respectively, making it the only cancer with an overall 5-year survival rate in the single digits. Even for those people diagnosed with local disease, 5-year survival is only 22%. More than half of patients are diagnosed at a distant stage, for which 5-year survival is 2%.

Incidence and Mortality: Each year nearly 44,000 people in the United States will be diagnosed with pancreatic cancer, and more than 37,000 will die. Worldwide, more than 278,000 people will be diagnosed, and nearly 267,000 will die of the disease. The incidence of pancreatic cancer is rising, and some reports project that the number of new pancreatic cancer cases and pancreatic cancer deaths will more than double by 2030.

Detection/Diagnosis: Pancreatic cancer is very difficult to predict or to diagnose at early stages of disease. It often develops without early symptoms, there is no widely used method for early detection, and, although some risk factors have been identified (such as tobacco use, family history of pancreatic cancer, and a personal history of pancreatitis, diabetes, or obesity), few patients diagnosed with pancreatic cancer have identifiable risk factors.

Treatment: The only curative treatment for pancreatic cancer is complete surgical resection. Unfortunately, fewer than 20% of patients are candidates for surgery, because pancreatic cancer is usually detected after it has spread. Cancers that cannot be treated with surgery are called “unresectable.” For those patients with localized disease and small cancers with no lymph node metastases and no extension beyond the capsule of the pancreas, complete surgical resection can yield 5-year survival rates of 18% to 24%. Approximately 80% of patients who undergo surgery eventually relapse and die from the disease, suggesting a need for effective strategies to eradicate minimal residual disease following surgery to prevent relapse. For patients who undergo surgery, adjuvant treatment with the chemotherapy drug gemcitabine lengthens survival. The targeted anti-cancer drug erlotinib (Tarceva®) has also demonstrated a small improvement in advanced pancreatic cancer survival when used in combination with gemcitabine.  More recently, combination chemotherapy with FOLFIRINOX has shown an overall survival (OS) benefit of approximately 11 months versus about 6.5 months for gemcitabine alone, and gemcitabine plus abraxane has shown an OS of 8.5 versus 6.5 for gemcitabine. Thus, for cancers that are unresectable, treatments including chemotherapy and targeted therapy may be able to control the disease and help patients live longer and feel better. Unfortunately, these treatments have not been shown to achieve longer term survival.


When Are Clinical Trials Recommended?

Because of the poor prognosis and lack of effective treatment options, for pancreatic cancer a clinical trial is nearly always preferred over existing treatment options for everything except localized tumors that can be removed surgically. Specifically, pancreatic cancer patients are encouraged to participate in clinical trials:

  • As adjuvant treatment after surgery for local disease
  • When pancreatic cancer returns after surgery
  • For unresectable disease (locally advanced cancer that cannot be treated by surgery), when patient is in good condition (has a good performance status)
  • After first-line treatment for locally advanced cancer or metastatic, if the patient has good performance status

Go to our Clinical Trial Finder to find clinical trials of immunotherapies for pancreatic cancer that are currently enrolling patients.


Why Consider Immunotherapy For Pancreatic Cancer?

Pancreatic cancer is characterized by a highly immunosuppressive environment, with multiple components and pathways that inhibit effective pancreatic cancer-targeted immune responses. Because of this, however, there is great potential to target these mechanisms of immunosuppression and reverse them to create an environment that supports the infiltration of anti-tumor immune responses and enables the generation of T cells capable of killing pancreatic tumor cells. Each of these components and pathways represents a potential target for pancreatic cancer immunotherapy. Through ongoing research, CRI and other scientists are developing new treatments targeting one or more of these pathways to “re-program” the pancreatic cancer microenvironment to enable effective anti-cancer immune responses.


Promising Advances and CRI Impact

Several strategies to harness the immune system to treat pancreatic cancer are currently being explored in clinical and preclinical studies. Some that have received the greatest attention to date and that are showing promise include:

Antigen-Specific Immunotherapy

There are several antigen-specific immunotherapies, sometimes referred to as therapeutic vaccines, in clinical and preclinical testing for pancreatic cancer. Some of these target defined proteins that are commonly overexpressed in pancreatic cancer, such as mesothelin and mutated KRas, and others are composed of pancreatic cancer cell lines that may express several pancreatic cancer-related antigens. A number of these therapies have advanced to later-stage clinical trials, including HyperAcute-Pancreas and GVAX Pancreas vaccines, both for patients with surgically resected pancreatic cancer, and GVAX given with Ipilimumab for advanced pancreatic cancer patients.


This hematoxylin and eosin stained slide of a surgically removed (resected) primary pancreatic tumor shows a cluster of immune cells (lymphoid aggregate) observed next to a pancreatic tumor lesion in a patient treated with a GM-CSF vaccine 2 weeks before surgical removal of the primary tumor. Immunohistochemistry of this and similar aggregates found throughout the resected tumor shows CD4+ and CD8+ T cells—aka helper T cells and killer T cells, respectively—with B cells in germinal center-like structures. (Photo courtesy of Lei Zheng and Elizabeth Jaffee, Johns Hopkins University)


Targeting CD40

Studies with activating antibodies targeting the CD40 molecule have shown the ability to alter suppressive immune cells in the pancreatic cancer microenvironment, called tumor-associated macrophages (TAMs). The antibodies shift TAMs from a pro-cancer to an anti-cancer state, enabling the destruction of tumor stroma and allowing improved access by other immune cells and cytotoxic drugs.

An early clinical trial of an antibody targeting the CD40 molecule (CP-870,893) showed promising results in patients with metastatic pancreatic cancer. Of 21 patients treated with the anti-CD40 antibody, plus the chemotherapy gemcitabine, 5 patients (24%) had a partial response and 11 patients (52%) showed stable disease, resulting in an overall clinical benefit rate of more than 75%. Treatment with the anti-CD40 antibody also demonstrated increased median progression-free survival (5.6 months v. 2.3 months with gemcitabine alone) and overall survival (7.4 months v. 5.7 months with gemcitabine alone). Another phase I trial of CP-870-893 is currently recruiting for patients who are surgically resectable.

Adoptive T Cell Therapies

Adoptive immunotherapy involves harvesting T cells from a patient, growing them to vast numbers in the laboratory, and re-infusing them into the patient; sometimes this also involves genetically modifying the T cells prior to laboratory expansion and re-infusion. One area that is gaining attention is adoptive therapy with chimeric antigen receptor (CAR) T cells. These are cells that have been genetically engineered to express chimeric antigen receptors, which have two components, one to help the T cells recognize a certain cancer-specific molecule, and the other to activate the T cell once it comes into contact with that molecule. This type of therapy has shown great promise in certain blood cancers, including some life-saving results in chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL), and is now being explored for its potential to treat pancreatic cancer.

CRI-funded researcher Carl June, M.D., who led the trials in CLL and ALL, is exploring the potential of CAR T cells modified to recognize mesothelin, which is expressed in all pancreatic cancers but not in healthy pancreatic cells, to treat patients with pancreatic cancer. Steven Rosenberg, M.D., Ph.D., is also exploring this approach in a phase I/II clinical trial at the National Cancer Institute.

Another approach to CAR T cell therapy involves targeting the fibroblast activation protein (FAP), which is selectively expressed by pancreatic tumor stromal cells. Scientists hypothesize that FAP+ stromal cells recruit and educate suppressive immune cells. In models, elimination of FAP+ stromal cells has been shown to enhance the efficacy of therapeutic vaccination and inhibit tumor growth. In a current study, CRI-funded graduate student Albert Lo is working to validate FAP+ stromal cells as candidate targets for pancreatic cancer immunotherapy through preclinical studies of adoptive therapy with CAR T cells modified to target FAP.

CRI Fellow Ingunn M. Stromnes, Ph.D., is also conducting preclinical studies to develop and evaluate strategies using adoptive therapy with tumor-reactive T cells to destroy pancreatic tumors, including the use of T cells targeted to the mesothelin protein.

Interleukin 15 (IL-15)

In 2008, several CRI investigators were part of a multi-institutional preclinical study showing that treatment with the immune activating molecule interleukin 15 (IL-15), when complexed with its receptor, could trigger rapid regression of established pancreatic cancers and significantly prolong survival. They found that destruction of the cancer was mediated by killer T cells residing in the tumor rather than newly infiltrating killer T cells. This suggests that treatment with IL-15 can successfully relieve tumor-resident killer T cells from functional suppression and reactivate them to kill pancreatic cancer cells. A phase I clinical trial to test IL-15 treatment in patients with pancreatic cancer began in 2012.

GM-CSF

In 2012, two CRI-funded researchers independently showed that the mutation in the KRas gene—which is mutated in nearly all pancreatic cancers—triggers expression of the immune molecule GM-CSF. They further found that tumor-derived GM-CSF recruits immature immune cells and turns them into suppressive immune cells, and that by blocking GM-CSF they could inhibit the suppressor cells and enable the immune system to fight the tumors. Because KRas mutations and tumor-promoting inflammation are associated from the earliest stages of pancreatic cancer, strategies to specifically target GM-CSF may offer the possibility of delaying or reversing inflammation-driven pancreatic cancer progression.


Sources: National Cancer Institute Physician Data Query (PDQ), American Cancer Society Facts & Figures 2012, National Comprehensive Cancer Network (NCCN) Guidelines for Patients, “The Alarming Rise of Pancreatic Cancer Deaths in the United States: Why we need to stem the tide today” (Pancreatic Cancer Action Network), ClinicalTrials.gov, CRI grantee progress reports

 

Pancreatic Cancer News & Stories

Reviewed By:

Elizabeth Jaffee is an expert in pancreatic cancer immunotherapy at The Johns Hopkins University.
Elizabeth Jaffee, M.D.
Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD

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