Immunogenic mutations: Cancer’s Achilles heel

In the 1890s, a surgical oncologist named William Coley first attempted to harness the immune system to fight cancer. He injected a mixture of bacterial strains into patient tumors, and occasionally, the tumors disappeared. The treatment was termed “Coley’s Toxins,” and although treatments only rarely resolved cancer cases, it launched a long investigation into anti-tumor immunity.

Fast forward 120 years to the 2010s, and a new series of anti-cancer immunotherapeutic agents have been approved for use in humans. Arguably the most successful of these are “immune checkpoint blockade” antibodies. These agents release the brakes on immune cells called T cells, which recognize antigens on tumors and kill cancer cells (image below). When used to treat cancer patients who have failed all other treatments, a remarkable number of patients are experiencing long term remissions and in some cases, may be cured. However, the specific tumor antigens that T cells recognize remain largely unknown.

Tumor mutations are one possible source of antigens. Cancer is a disease of mutations, or changes in the DNA code, that allow tumor cells to replicate, avoid death, and spread throughout the body. The human genome contains three billion letters in the DNA code, but tumors typically harbor only a few dozen to a few hundred mutations. Historically, searching for mutations was akin to searching for the proverbial needle in a haystack. However, mutations represent ideal therapeutic targets since they are completely tumor restricted, so researchers continued to search for ways to identify the full breadth of mutations within tumors.

2008 saw a giant step forward, when an entire tumor genome was sequenced for the first time; since then, tens of thousands of tumors have been sequenced. These studies have revealed that every tumor has a unique set of mutations, and most tumors use unique pathways to tumorigenisis. For this reason, DNA sequencing has begun to guide personalized cancer treatments. In some cases, oncologists have found a therapeutically actionable mutation and have prescribed a drug that otherwise would not have been considered. For example, a blood pressure medication was used to eradicate a colorectal tumor in one patient. However, for most patients, the mutations present within their tumors are not targetable with existing drugs.

Enter cancer immunotherapy. The vast array of tumor mutations that are not “druggable” may nonetheless be targetable with immunotherapy. The new genomic sequencing technologies that have shed light on how tumors grow also help identify mutated antigens that T cells recognize. Multiple lines of evidence point to mutations as critical targets that lead to immune mediated cancer regression. For example, tumors with higher numbers of mutations respond better to immune treatments than tumors with few mutations. Also, patients that respond well to T cell based therapies often have T cells that recognize mutations.

With these studies in mind, researchers attempted to target mouse tumor mutations with vaccines. For example, one group sequenced the DNA of a mouse tumor and identified tumor-specific mutations; they then custom designed vaccines to activate T cells that recognized the specific mutated antigen found in the tumor. When they injected the mice with these vaccines, the tumors completely dissolved.

Based on such studies, several companies have been founded to design personalized vaccines targeting mutations. These companies sequence patient tumor DNA and then, for each patient, construct a unique vaccination formula that is designed to activate mutation-specific T cell responses. The first results have begun to trickle in from patients who received this type of treatment. They showed that personalized vaccines successfully activated T cells that recognized patient-specific mutations. Time will tell whether these promising results lead to improved outcomes.

Advances in DNA sequencing technologies have finally provided an understanding of the antigens recognized by anti-cancer cells. Tumor mutations, only recently identifiable, seem to be the chink in the armor of cancer cells that allows the immune system to destroy tumors. Thus, DNA sequencing may go hand in hand with immunology in designing new cancer treatment options specifically targeting mutations. More than 100 years since the introduction of Coley’s Toxins, we are now in a position to realize William Coley’s vision of fighting cancer with the immune system.

Featured image credit: ‘Granuloma Cell Tumour of the Ovary’ by Ed Uthman. CC BY 2.0 via Flickr.