Throughout the month of June and in celebration of the Cancer Research Institute's 65 years of pioneering leadership in the field of cancer immunology, we are sharing 30 of the most important scientific breakthroughs made possible with CRI funding. Just like the past three weeks, we’ll provide some background and context for these advancements.
This week we're highlighting breakthroughs that focus on the benefits of bacteria, vaccines, and the use of immunotherapy earlier in the course of treatment. To look back on Cancer Immunotherapy Month and our 30 Days of CRI Impact, check #CIM18 on Twitter.
2018: CRI-SU2C Immunology Dream Team
Lung cancer kills more people in the United Stated than any other cancer. While most lung tumors can be removed, most patients still relapse later after surgery. To address that, this study—conducted by members of the CRI-SU2C Immunology Dream Team—treated patients with anti-PD-1 checkpoint immunotherapy before surgery. Remarkably, they found that nearly half these patients had major responses prior to their tumors being resected. While more time and studies will be necessary to reveal the true long-term benefit, thus far immunotherapy appeared to provide significant protection against relapse too. In the words of study leader Dr. Drew Pardoll, of the Johns Hopkins School of Medicine, “we are very optimistic that this approach will eventually be practice-changing and may augment or even replace chemotherapy prior to surgical resection.”
1974: Dr. Edgar Lederer
When we think of microscopic organisms such as bacteria, viruses, and fungi within us—referred to collectively as the microbiome—we mostly think of negative associations such as diseases and infections that some species cause. However, because of their ability to stimulate the immune system, bacteria, specifically, can also help promote immune responses against cancer. In fact, the first ever use of immunotherapy—in the 1890s by CRI’s “grandfather” Dr. William B. Coley—involved infecting cancer patients with bacteria. In 1974, Dr. Edgar Lederer of the University of Paris-Sud revealed how specific components of bacterial cell walls called peptidoglycans are able to stimulate immunity and even characterized the minimal structural requirements necessary for this immune-boosting activity. In fact, bacille Calmette-Guerin (BCG)—the first immunotherapy ever approved by the FDA, in 1990—exploited the immune-stimulating properties of bacteria to effectively treat patients with early stage bladder cancer.
2008: Drs. Nicolas Manel and Dan Littman
In addition to stimulating immune responses, bacteria also play important roles in other aspects of the development and activity of the immune system. One way, which was discovered by Drs. Nicolas Manel and Dan Littman of the New York University School of Medicine, involves specialized immune cells called Th17 cells. In particular, they found that the presence of bacteria called cytophaga-flavobacter-bacteroidetes was associated with, and potentially were even required, for the development of these IL17-producing T helper cells. When these bacteria were absent, it skewed the ratio of Th17 cells to regulatory T cells, which can influence intestinal immunity, tolerance, and susceptibility to inflammatory bowel diseases.
2015: Drs. Leticia Corrales and Thomas Gajewski
More recently, the role that bacteria can play in immunotherapy was revealed by Drs. Leticia Corrales and Thomas Gajewski. In their breakthrough work, they discovered that bacteria in one part of the body can influence how the body responds to cancer elsewhere, in this case melanoma. Even without additional treatment, mice that possessed “good” bacteria (Bifidobacterium) displayed superior protection against tumor. Additionally, when these mice were treated with anti-PD-1 checkpoint immunotherapy, it “nearly abolished their tumor growth.” While these studies were performed in mice, follow-up studies led by Dr. Gajewski showed that this same connection existed in human cancer patients as well. These insights subsequently led to the development of a number of approaches aimed at utilizing the microbiome to enhance the success of cancer immunotherapy for patients, some of which are now being investigated in the clinic.
1993: Dr. Pramod Srivastava
The immune system’s power against cancer comes from its ability to recognize and identify mutated tumor proteins, and there are several factors that can help promote this activity. One such factor was highlighted by Dr. Pramod Srivastava, who showed that a mixture of heat shock protein 70 (hsp70) with tumor cells was able to render mice immune to future challenges with those tumor cells. In this work, he also showed that hsp70 itself didn’t stimulate immunity directly, but did so by binding to mutated tumor peptides and enabling easier recognition by the immune system. As a result, HSPs have been incorporated into vaccines such as OncoPhage, which was developed by Dr. Srivastava and was approved in Russia in 2008 for kidney cancer.
2012: Drs. Matthew Vesely and Robert Schreiber
What differentiates tumor cells from normal cells are the proteins they express, especially the abnormal proteins that result from the genetic mutations they accumulate. However, until recently, it hadn’t been shown that these mutations could be quickly identified and targeted via vaccines. Fortunately, Drs. Matthew Vesely and Robert Schreiber demonstrated for the first time that it was possible to identify which mutated proteins were produced by cancer cells and that vaccines could be used to target them in mice. Now, these personalized immunotherapies (known as neoantigen vaccines), which can potentially teach individual patients’ immune systems what their individual tumors “look like,” are being evaluated in the clinic, and thus far have shown promising preliminary success.
2017: Drs. Sacha Gnjatic and Kunle Odunsi
While tumors express many abnormal proteins that arise from mutations, other times they express normal proteins inappropriately. In particular, proteins encoded by the cancer-testis genes are normally only expressed during development or in adult testicular cells; however, cancer cells sometimes aberrantly turn their expression back on. One protein in this group is called NY-ESO-1, which is commonly expressed in several cancer types, especially ovarian cancer, where tumors that express this protein are typically more aggressive and associated with lower survival. As a result, vaccines that target NY-ESO-1 have been developed and used to treat these patients. Impressively, in this work by Dr. Kunle Odunsi of the Roswell Park Cancer Institute and Dr. Sacha Gnjatic of the Icahn School of Medicine at Mt. Sinai, they found that patients with NY-ESO-1-expressing tumors who received a vaccine targeting NY-ESO-1 lived longer than patients who didn’t receive the vaccine by an average of more than two years. These promising results demonstrate the immense potential of cancer vaccines, whose benefits should only continue to increase as methods to select the best vaccine targets are refined and improved.
Thank you for following our 30 Days of CRI Impact and celebrating 65 years of pioneering leadership in the field of cancer immunology this June.