Treatment and Prevention of Pancreatic Cancer with Cancer Vaccines

Over the past year, there have been promising results from multiple early stage clinical trials evaluating cancer vaccines, one type of immunotherapy, in pancreatic cancer patients. From the AMPLIFY-201 trial evaluating ELI-002 2P co-led by Dr. Zev Wainberg from the UCLA Agi Hirshberg Center for Pancreatic Diseases, to the Memorial Sloan Kettering developed autogene cevumeran, to the most recent results with mKRAS-VAX out of Johns Hopkins University School of Medicine, the ability to stimulate the immune system against pancreatic cancer has been demonstrated. Additionally, these results are an encouraging step forward for immunotherapy which, so far, had not been effective for pancreatic cancer.

But what is a cancer vaccine and how do these approaches differ from each other? From “off-the-shelf” to personalized vaccines, this article explains what cancer vaccines are, how they work, and the types of vaccines that are currently being assessed in pancreatic cancer.

What is immunotherapy and why hasn’t it worked for pancreatic cancer?

Immunotherapy is a type of treatment that harnesses a person’s immune system to help defeat cancer. The most successful immunotherapy, immune checkpoint inhibition (ICI) works by blocking immunosuppressive signals from the tumor which allows the immune system to identify and destroy cancer cells. Pancreatic cancer is known to have a heavily immunosuppressive tumor microenvironment that includes stromal cells surrounding it which has limited the effectiveness of ICI therapy. The combination of ICI with therapies that actively stimulate the immune system may be a better way to achieve an anti-tumor immune response in pancreatic cancer. Cancer vaccines are emerging as an option to train and activate the immune system to respond to cancer.

What are vaccines and how do they work?

Vaccines train the immune system, specifically an immune cell type called T cells, to detect and then destroy pathogen infected cells. While vaccines are commonly associated with viral or bacterial infections, they can also train the immune system to recognize tumor cells.

Vaccines introduce markers that the body recognizes as harmful, called antigens, to the immune system. Antigens get taken up by specialized immune cells called antigen presenting cells that then display the antigen to T cells for recognition. T cells become activated and begin to multiply to mount an immune response as well as develop a memory of the antigen. Activated T cells can identify cells that express the antigen and destroy them. In the future, when memory T cells encounter the same antigen again, they are poised to respond quickly and mount an aggressive response to eliminate it.

What are cancer vaccines?

Cancer vaccines expose the immune system to cancer antigens allowing T cells to detect and destroy tumor cells while not attacking healthy cells.

Cancer antigens can be:

• Tumor-associated antigens which are proteins that are highly expressed by tumor cells and expressed much less on healthy cells
• Tumor-specific antigens or neoantigens which are proteins produced by genes with genetic mutations and only expressed in tumor cells
• Viral antigens which are viral proteins expressed by tumor cells in cancers caused by viruses (such as HPV and cervical cancer)

Antigens in viruses can be made from different materials:

• Peptides are short pieces of proteins
• DNA/RNA is the blueprint or code that cells use to build proteins
• Whole Tumor Cells is a mixture of all the proteins from a tumor cell

Most of the current vaccines being clinically evaluated for pancreatic cancer are either peptide or RNA vaccines. Both peptides and RNA can be made in the lab and personalized to a specific patient (see personalized neoantigen vaccine below).

What types of cancer vaccines are being evaluated in pancreatic cancer?

All the current cancer vaccines being evaluated for pancreatic cancer are neoantigen vaccines. They train immune cells to detect tumor-specific proteins produced by mutated genes in tumors to find and destroy pancreatic tumor cells. There are two types of neoantigen vaccines that are currently being clinically tested for pancreatic cancer.

Personalized neoantigen vaccines

Every tumor is different which means the neoantigens expressed by one person’s tumor may not be shared with another. A personalized tumor vaccine is made to target the specific neoantigens that are expressed by that patient’s tumor.

To generate this type of vaccine, the patient’s tumor is removed and its DNA is sequenced to identify the neoantigens it may express. A vaccine is then generated to target an array of neoantigens present in that specific tumor. This process is both expensive and takes time for the vaccine to be generated.

Mutant KRAS targeted vaccines

Over 90% of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, are caused by mutations in the KRAS gene. This means that the majority of people with pancreatic cancer have tumors that express mutant KRAS protein and could potentially be treated with a vaccine that targets mutant KRAS.

This type of vaccine, where one design can treat many people, has been termed “off-the-shelf” because it can be mass produced and available on demand. While there are multiple mutations in KRAS that cause PDAC, all of the current vaccines being evaluated target more than one of KRAS mutations to increase the population that they can treat.

How are cancer vaccines being evaluated in pancreatic cancer clinical trials?

The phase 1 clinical trials for ELI-002 2P, autogene cevumeran, XP-004, and mKRAS-VAX assessed the use of cancer vaccines in patients with resectable pancreatic cancer, after surgery and in combination with either chemotherapy, ICI, or both. The goal is that the cancer vaccine will train the immune system to identify and be able to destroy any cancer cells that remain after surgery. In a separate phase 1 clinical trial, mKRAS-VAX was evaluated in people with a family history of pancreatic cancer and who had a pancreatic lesion in hopes of preventing the disease from developing.

These early results, while promising, highlight the need for continued studies in using cancer vaccines for pancreatic cancer. Larger studies with longer follow-up are needed to understand how these early results translate to the larger pancreatic cancer population. Understanding how and why one patient responds to a cancer vaccine while a second patient does not and whether these induced immune responses develop into long-term disease control are questions still to be answered.