Jefferson Colorectal Cancer Vaccine Study Promising Results

Colorectal Cancer

Jefferson researchers recently completed a Phase I colorectal cancer vaccine study and the results, published in the Journal of ImmunoTherapy of Cancer, were promising. Participating patients evidenced no signs of serious adverse events and samples of their blood contained markers of immune activation. This represents an early indication the vaccine could activate immune cells to fight colorectal tumors and metastases. More research is gearing up to test if the vaccine is effective at slowing tumor growth.

Colon cancer, on the rise, represents the second highest cause of cancer deaths in the US and worldwide. Surgery can potentially cure the disease in many patients as reported in the Jefferson press release published in EurekAlert!  However, the prognosis is bad for those with recurrence of their disease. The Jefferson (Philadelphia University + Thomas Jefferson University) team developed the vaccine to train the patient’s immune system to attack the colon cancer that had spread pre surgery. The core focus of this pivotal phase I study was determining if directing a patient’s immune system to combat this type of cancer was possible.

Investigator Karen E. Knudsen, PhD, EVP of Oncology Services and Director of the Sidney Kimmel Cancer Center, Jefferson Health noted “this is a true milestone—made possible by the scientists and clinicians in our colorectal cancer team working in synchrony.”

The Phase I Trial Background

The actual trial was designed to face the unmet need for improved therapeutic paradigms in colorectal cancer, the 3rd leading cause of cancer and 2nd leading cause of cancer mortality worldwide.

This need is underscored by the populations in jeopardy, including the ~100 million people in the US over 50 years of age that have a 1:8 risk associated with a disease-specific mortality of 50%. Mortality reflects metastatic disease: ~50% of patients initially present with regional or distant metastases, while ~20% present with occult metastases. Beyond the general population risk, there is an established stage-specific difference in outcomes in pN0 (node negative) African Americans with colorectal cancer, who exhibit ~40% excess mortality attributable to race. Reductions in mortality have been hampered by the absence of effective chemo-, radio-, and immuno- therapeutic approaches to metastatic disease. In that context, immunotherapy has been disappointing, in part, reflecting the absence of antigens that are tumor-specific, immunogenic, and universally associated with neoplasia.

Moreover, the gap in survival between African Americans and Caucasians specifically reflects the inability to identify those with occult metastases who are at increased risk for developing recurrent disease. This study advances an emerging paradigm in colorectal cancer cell detection and eradication, employing GCC as a molecular marker and immunological target. GCC is a protein whose expression is normally restricted to intestinal epithelial cells, but universally expressed by metastatic colorectal tumors. We have clinically validated the detection of occult metastases in lymph nodes by quantifying GCC mRNA (messenger RNA) by reverse transcriptase (RT)-PCR (qRT-PCR). This study revealed that occult metastases were the most powerful independent predictors of survival in pN0 patients. Further, there is a disproportionate burden of occult disease in African American, compared to Caucasian, patients. This new molecular staging platform provides a unique opportunity to identify occult metastases underlying racial disparities in disease recurrence, which could be prevented by tumor-targeted immunotherapy.

In the absence of ideal tumor antigens, immunotherapy has been directed to tissue-specific proteins. Barriers to employing self-antigens include tolerance, which limits anti-tumor immunity, and autoimmunity. The present study advances an emerging paradigm exploiting immunological compartmentalization of mucosally-restricted antigens to generate systemic antitumor immunity without autoimmunity.

Asymmetry in immunological cross-talk between compartments, wherein systemic T and B cell responses rarely extend to mucosae, suggest that proteins normally expressed in mucosae, but which are expressed systemically by tumors, may serve as vaccine targets for metastases. Advantages of these cancer mucosa antigens include unique systemic immunoreactivity profiles supporting highly effective durable antitumor immunity in the context of absent immunological cross-talk between compartments restricting autoimmunity.

Here, this paradigm will be advanced employing the tumor marker GCC, which induces immune responses that oppose metastatic colorectal cancer in preclinical models, without autoimmunity. This study will define the safety and immunological efficacy of adenoviral GCC vaccine in African American and Caucasian pN0 colon cancer patients with excess recurrence risk reflecting occult lymph node metastases identified by GCC qRT-PCR. This study will be the first step in translating GCC into a vaccine for the secondary prevention of metastases in African American and Caucasian colorectal cancer patients.

The  GUCY2C Antigen Identified by Dr. Scott Waldman

The Jefferson team first studied the vaccine using mice.  Historically, tumor vaccines are developed against a kind of molecular sign-post for cancer. Cancer cells share nearly all of the same molecules making it difficult for the immune system to differentiate the normal from the cancerous.  Tumor antigens are molecules that the immune system recognizes as different from normal.  For colorectal cancer, one such antigen was  GUCY2C, identified by Scott Waldman, MD, PhD, which formed the basis of the vaccine.

Vaccine Development

Adam Snook, PhD, Assistant Professor in the Department of Pharmacology and Experimental Therapeutics, collaborated with Dr. Waldman and team by activating the immune system against the GUCY2C molecule.  The team collaborated to  join the GUCY2C molecule with PADRE, a molecule that boosts the immune reaction—loaded into an adenovirus vector —hence engineering a vaccine that could specifically target the colon cancer.

 Phase I Study Summary

The Phase I trial enrolled 10 patients with stage I or II colon cancer.  The investigators administered one dose per patient.  Patients came back for blood draws 30, 90, 180 days after immunization. Although some patients  experienced some discomfort at the location of injection, no serious side effects were reported.  The investigative team found that the blood samples of the patients revealed activation of “killer T cells,” the immune cell type the researchers had expected.  As reported in the Jefferson press release, the killer T cells are tasked with finding and destroying colon cancer cells that are responsible for causing the cancer to come back.

Next Steps

The research team will conduct a Phase II study starting the fall of 2019.  The investigators also observed that GUCY2C is expressed by other deadly cancers including gastric, esophageal, and pancreatic cancer.   The team noted in the press release that these four cancers represent the root of 20% of all cancer-related deaths. Hence, Dr. Snook commented that “the goal of the study to begin this fall is to show that version 2.0 of the vaccine is even better and that it may benefit a much bigger group of the overall cancer patient population.”

Trial Financial Support

The Jefferson study was funded by the following organizations:

  • National Institutes of Health (NIH) R01 CA170533 (public funds)
  • Targeted Diagnostic and Therapeutics Inc. (industry sponsor)
  • PhRMA Foundation
  • Margaret Q. Ladenberger Research Foundation
  • Mignon Dubbs Fellowship Fund
  • Pennsylvania Department of Health

Lead Research/Investigators

Scott Waldman, MD, PhD

Adam Snook, PhD, Assistant Professor in the Department of Pharmacology and Experimental Therapeutics

Karen E. Knudsen, PhD, EVP of Oncology Services and Director of the Sidney Kimmel Cancer Center