Unlocking the Promise of Vaccines for Cancer Treatment

Read part 1 and part 2.

From checkpoint inhibitors to chimeric antigen receptor (CAR) T-cell therapies, the cancer landscape has seen immense innovation in recent years. However, vaccines have not been among these innovative technologies.

To date, there is just 1 approved vaccine for the treatment of cancer: sipuleucel-T (Provenge). The vaccine, approved in April 2010, is used for the treatment of patients with advanced prostate cancer who have stopped responding to hormone therapy. While it does not cure cancer, it has been shown to extend survival by approximately 4 months. In the IMPACT trial, which led to the vaccine’s approval, the proportion of patients receiving the vaccine who were alive at 3 years was 50% higher than that in the control group¹.

With only sipuleucel-T on the market, researchers are involved in a myriad of trials assessing the safety and efficacy of various types of vaccine candidates, including:

• Tumor cell vaccines, which are made from patient’s cancer cells that have been removed during surgery. The cells are altered and then injected back into the patient so that the immune system attacks the cells and any other similar cells in the body.
• Antigen vaccines, which boost the immune system by using 1 antigen.
• Dendritic cell vaccines, in which immune cells from the patient’s blood are removed and exposed in the lab to cancer cells or cancer antigens that then turn the cells into dendritic cells and help them grow. They are then injected back into the patient and create an immune response.
• Vector-based vaccines, which cause vectors to make them more effective.

Reflecting on lessons learned and new understandings of cancer biology, researchers have not lost hope that vaccines can play an integral role in cancer treatment. Over the last 6 months, several trials have made headlines for their preliminary, but promising, results.

A preliminary study from Mount Sinai leveraged a vaccine that stimulated dendritic cells to attack tumors. In the study of 11 patients with indolent non-Hodgkin lymphoma (iNHL), the vaccine was injected directly into tumors. Typically, checkpoint blockade therapy doesn’t work in this type of cancer. Six patients experienced stable disease, 2 had partial remission, and 1 had complete remission. Understanding that for some reason T-cells don’t seem to recognize iNHL, the treatment regimen included a human protein form of FMS-like tyrosine kinase-3 ligand, radiotherapy, and a Toll-like receptor (TLR) agonist, in this case TLR3, to stimulate dendritic cells to attack the cancer.

The researchers also tested the vaccine in combination with checkpoint blockade therapy in mine, finding that when mice with iNHL were given checkpoint blockade therapy alone, it did not work. In combination with the vaccine, 75% of the mice went into remission.

Based on results from the study, the vaccine is undergoing trials in breast and head and neck cancer by focusing on neoantigens in a patient’s cancer.

Reasons for why vaccines haven’t had as much success as other methods of treatment depends on who you ask. In an interview with The American Journal of Managed Care^® (AJMC^®), Adam Snook, PhD, assistant professor in the Department of Pharmacology and Experimental Therapeutics, at Jefferson (Philadelphia University and Thomas Jefferson University), explained that the majority of vaccine candidates have traditionally focused on patients with metastatic disease who don’t have as much of an opportunity to benefit. Similar to how CAR T-cell therapies are geared toward patients with advanced stage disease, vaccines have the opportunity to work the same way by finding their niche. For Snook, this is in the adjuvant setting.

Snook and researchers at Jefferson have developed a colorectal cancer vaccine, which has demonstrated promising results in a phase 1 trial.

“Our vaccine is focused on the group of patients that have surgery and have about a 50% chance of their disease coming back,” explained Snook. “So, we vaccinate to clean up the residual cancer cells that might be left to prevent it from recurring.”

The vaccine targets the GUCY2C molecule, which is present in intestinal epithelial cells. According to Snook, when these cells are infected by colon cancer, they keep expressing the molecule, and when the cancer spreads to other places in the body, the molecule stays with it. As a result, GUCY2C has been identified as an important biomarker in the disease. The researchers combined the GUCY2C molecule with a molecule that boosts immune response and loaded it into an adenovirus vector.

The benefit of having the vaccine is its potential for efficacy long term, said Snook. While chemotherapy stops working once therapy is completed, vaccines can induce an immune response that lasts for years or decades. In addition to sustained efficacy, vaccines also offer fewer side effects than chemotherapy, which is often used following tumor resection to prevent recurrence.

The clinical trial enrolled 10 patients with stage 1 or stage 2 colon cancer who received 1 dose and then came back for blood draws at 30, 90, and 180 days following vaccination. During the study period, patients experienced discomfort at the site of injection, but there were no serious side effects reported. The researchers also observed that the vaccine was able to elicit an immune response and activate killer T-cells in about half the patients.

Since starting the trial, the researchers found that other intestinal cancers express the GUCY2C molecule, including gastric, esophageal, and pancreatic cancer. Moving forward, the researchers have modified the vaccine to try and improve response rates and are preparing for a phase 2 trial that will include the modified vaccine and patients with the 4 different types of cancer.

For Ezra Cohen, MD, FRCPSC, FASCO, medical oncologist and associate director of Translational Science at Moores Cancer Center, and professor of medicine at University of California San Diego Health, previous and current vaccines have failed because they've largely ignored the biology, often searching for common tumor antigens that are likely irrelevant to the biology of a patient’s cancer and immune response, he explained in an interview with AJMC^®.

Cohen and researchers from the University of California San Diego Health and La Jolla Institute for Allergy and Immunology are working on a vaccine in the metastatic setting that’s specific to each patient’s cancer.

“About 4 years ago, we began thinking: we know every cancer is different at a molecular level, and we know everyone’s immune system responds differently to different antigens, and given these 2 facts, designing therapies that are ignoring that biology are never going to get us to where we want to be, which, boldly, is curing metastatic disease,” said Cohen.

Once the neoantigens in a patient’s cancer are identified, the researchers then identify peptides that can be utilized to create a vaccine to stimulate an immune response. The vaccination is used in combination with pembrolizumab (Keytruda) to boost initial immune response.

The phase 1b study is currently enrolling 10 patients to test the personalized vaccine. The first patient enrolled in the study, who has stage 4 pancreatic neuroendocrine cancer, has had stable disease since September when she began receiving the 3 doses of the vaccine each 3 weeks apart. According to Cohen, a biopsy showed that the mutations she was immunized against from the vaccine were gone. The 1 remaining mutation that the researchers could not create the peptide for was still there, almost serving as a positive control, he explained.

Along the way, the researchers have learned how to tweak the vaccine to potentially make it more effective. In a preclinical model, they noticed that by initially clustering the vaccine and giving 3 doses each a week apart and then administering 3 more doses each 3 weeks apart, there was a better immune response.

Reference

Cheever M, Higano C. PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine [published online June 2011]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-10-3126.