Biotechniques
08/27/2015 Nathan Blow, PhD
Engaging the immune system to attack tumors could be key in the war on cancer. Nathan Blow looks at what it takes to turn our bodies into cancer fighters.
It started with a simple observation. During their experiments in mice in the late 1980s, a small group of immunologists working at Centre d’Immunologie INSERM-CNRS in France uncovered a new receptor located on the T cell surface, one that they called cytoxic T-lymphocyte antigen 4 ( CTLA-4). Finding a new T cell surface receptor was obviously a big deal since it could open doors to understanding how T cells interact with other immune cells and create a large number of experimental possibilities for researchers around the globe. With their results and data in hand, the INSERM team published their initial CTLA-4 findings in late 1987 in the pages of Nature (1).
While an exciting find for immunologists, the Nature article also caught the attention of a scientist working half a world away in the Cancer Research Laboratory at the University of California, Berkley. James Allison directed the lab at the time, but his primary research interest was in understanding the interactions between the immune system and tumor cells. Upon reading the INSERM group’s paper, Allison grew curious about the function of CTLA-4, wondering if it might be connected to the body’s immune surveillance of cancer cells.
Since the 1950s, studies have demonstrated that the immune system has the potential to recognize and reject tumors. But the question for many was how, exactly, the immune system accomplishes such a feat. Without understanding how, there was no way to effectively harness the immune response in a fight against a growing tumor.
On the heels of the CTLA-4 description in Nature, another team published an article noting the close relationship between CTLA-4 and CD28 activated lymphocyte molecules. Allison followed up on this with an article showing that CD28 signaling co-stimulated murine T cells. Ensuing articles from Allison and other groups later pulled together the pieces and established that the CTLA-4 receptor was actually acting as an off-switch to stop T cells from attacking. But cancer cells could activate CTLA-4.
Shortly after, a critical study connecting CTLA-4 with a possible cancer therapy was published. In 1996, Allison and his colleagues reported for the first time in the journal Science that blocking CTLA-4 binding with an anti-CTLA-4 antibody made immune responses against tumors more effective (2). The body fought the cancer cells. The article sparked a renewed interest amongst researchers for finding ways to use the immune system to more effectively treat cancer. The age of immunotherapy began to emerge.
Taking Advantage of Our Immunity
CTLA-4 is an important piece of the immuno-oncology puzzle, but it is not the only piece that connects cancer cells to the immune system. Identifying other immune molecules that interact with cancer cells is an important focus for researchers at the moment as they hope to find new pathways towards creating novel immunotherapy options for patients by “revving” up the their immune systems.
Similar to CTLA-4, PD-1 is another receptor molecule that is expressed on the surface of T cells. PD-1, which stands for Programmed Cell Death 1, serves as an immune checkpoint regulating the activation of T cells. Over the last two decades, researchers have found that PD-1 is also similar to CTLA-4 in that it acts as a regulator of T cell activation and, also similar to CTLA-4, can be co-opted by cancer cells to avoid an immune response. Interestingly though, the intracellular signaling mechanisms of the two receptors appear to be different, facilitating the development of multiple immunotherapies targeting these particular receptors.
Bristol-Meyers Squibb has developed a monoclonal antibody-based anti-CTLA-4 treatment called ipilimumab that targets metastatic melanoma, while another human antibody, tremelimumab, has been under clinical investigation and trials in humans. Merck has developed a PD-1 blocking compound known as pembrolizumab for treating advanced melanoma; Bristol-Meyers Squibb also developed a PD-1 monoclonal antibody called nivolumab that was approved in 2014 to treat metastatic melanoma. In addition to these antibodies targeting PD-1, several other PD-1-based therapies are now in development. It’s also interesting to note that both Bristol-Meyers Squibb and Astra Zenca have been actively exploring whether or not the use of combinations of CTLA-4 and PD-1 blocking therapies could prove more effective in treating certain forms of cancer.
Personalizing the Fight
Carl June is taking another approach to developing new immunotherapies. Rather than focusing on developing antibodies or other molecules to interact with receptors naturally expressed on the T cell surface such as CTLA-4 or PD-1, June and other researchers have turned to engineering T cells to make them more active against cancer cells.
June, who is a professor at the Perelman School of Medicine and director of Translational Research in the Abramson Cancer Center at the University of Pennsylvania, is working on what has become known as chimeric antigen receptor (CAR) therapy. This idea dates back to the late 1980s when Zelig Eshhar, an immunologist at the Weizmann Institute of Science in Tel Aviv, developed the first CAR T cells. Shortly after he published the method, Eshhar visited the United States to work with Steven Rosenberg at the National Institutes of Health, where together they genetically engineered a T cell with specific cancer cell–targeting single-chain antibody variable regions. They then demonstrated that the redirected T cells could specifically lyse a human ovarian carcinoma cell line. Since that time, the design and construction of a variety of engineered T cells has led to several potential immunotherapy applications, some of which are now in clinical trials.
June’s work on CAR T cells led to one of the first T cell therapy clinical trials, CTL019, for B cell cancers such as B cell non-Hodgkin lymphoma and acute lymphoblastic leukemia. The idea behind CTL019 is to generate patient-specific T cells modified to express a protein that recognizes and binds CD19 on cancerous B cells. The initial results from the clinical trial, published in The New England Journal of Medicine in 2014, were encouraging: 30 patients with leukemia were treated with CAR T cell therapy, 27 went into remission for some length of time, 19 experienced continued remission, and 7 experienced recurrence (3). “However, because so few patients have been treated, and because those patients have been followed for a relatively short time, it is critical that more adult and pediatric patients are enrolled in the study to determine whether a larger group of patients with B cell cancers will have the same response, and maintain that response,” noted a University of Pennsylvania webpage describing the clinical trial efforts. Still, for the size of the study, the result made quite a strong impression on the scientific community.
“The patients who participated in these trials had relapsed as many as 4 times, including 60 percent whose cancers came back even after stem cell transplants. Their cancers were so aggressive they had no treatment options left,” Stephan Grupp, professor of Pediatrics at the Perelman School of Medicine and director of Translational Research in the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia, as well as lead investigator on the CTL019 trial, said in a press release following the 2014 publication. “The durable responses we have observed with CTL019 therapy are unprecedented.”
CTL019 has now pushed into a Phase II clinical trial, and June and the University of Pennsylvania are partnering with Novartis Pharmaceuticals to continue trials. On the heels of the strong CTL019 results, other companies, included Pfizer and Amgen, have started partnerships with other investigators developing CAR T cell immunotherapies.
It’s worth noting that immunotherapy, even though years in the making, is still a very new field of research. In 2013, Science magazine announced cancer immunotherapy as their scientific “Breakthrough of the Year,” but in an article announcing the winner, Jennifer Couzin-Frankel noted that their decision to pick immunotherapy actually became a topic of internal debate amongst the staff. “In celebrating cancer immunotherapy—harnessing the immune system to battle tumors—did we risk hyping an approach whose ultimate impact remains unknown?”, Couzin-Frankel wrote in her news article. Ultimately, they concluded that it passed the test as a major scientific breakthrough. Looking back now, immunotherapy has come a good way in two years. Scientists working on immunotherapy are shaping the way in which cancer research and treatment is being thought about. The field continues to evolve, moving treatment in exciting new directions with each discovery and clinical trial—a breakthrough indeed.
Editors Note: BioTechniques will be hosting an immuno-oncology webinar on October 6, 2015. Find out more...
References
1. Brunet, J.F. et al. 1987. “A new member of the immunoglobulin superfamily – CTLA-4” Nature. 328(6127):267-270.
2. Leach D.R., Krummel, M.F., and Allison, J.P. 1996. “Enhancement of antitumor immunity by CTLA-4 blockade” Science. 271(5256):1734-6.
3. Maude S.L. et al. 2014. “Chimeric antigen receptor T cells for sustained remissions in leukemia” N Engl J Med. 371(16):1507-17.
08/27/2015 Nathan Blow, PhD
Engaging the immune system to attack tumors could be key in the war on cancer. Nathan Blow looks at what it takes to turn our bodies into cancer fighters.
It started with a simple observation. During their experiments in mice in the late 1980s, a small group of immunologists working at Centre d’Immunologie INSERM-CNRS in France uncovered a new receptor located on the T cell surface, one that they called cytoxic T-lymphocyte antigen 4 ( CTLA-4). Finding a new T cell surface receptor was obviously a big deal since it could open doors to understanding how T cells interact with other immune cells and create a large number of experimental possibilities for researchers around the globe. With their results and data in hand, the INSERM team published their initial CTLA-4 findings in late 1987 in the pages of Nature (1).
While an exciting find for immunologists, the Nature article also caught the attention of a scientist working half a world away in the Cancer Research Laboratory at the University of California, Berkley. James Allison directed the lab at the time, but his primary research interest was in understanding the interactions between the immune system and tumor cells. Upon reading the INSERM group’s paper, Allison grew curious about the function of CTLA-4, wondering if it might be connected to the body’s immune surveillance of cancer cells.
Since the 1950s, studies have demonstrated that the immune system has the potential to recognize and reject tumors. But the question for many was how, exactly, the immune system accomplishes such a feat. Without understanding how, there was no way to effectively harness the immune response in a fight against a growing tumor.
On the heels of the CTLA-4 description in Nature, another team published an article noting the close relationship between CTLA-4 and CD28 activated lymphocyte molecules. Allison followed up on this with an article showing that CD28 signaling co-stimulated murine T cells. Ensuing articles from Allison and other groups later pulled together the pieces and established that the CTLA-4 receptor was actually acting as an off-switch to stop T cells from attacking. But cancer cells could activate CTLA-4.
Shortly after, a critical study connecting CTLA-4 with a possible cancer therapy was published. In 1996, Allison and his colleagues reported for the first time in the journal Science that blocking CTLA-4 binding with an anti-CTLA-4 antibody made immune responses against tumors more effective (2). The body fought the cancer cells. The article sparked a renewed interest amongst researchers for finding ways to use the immune system to more effectively treat cancer. The age of immunotherapy began to emerge.
Taking Advantage of Our Immunity
CTLA-4 is an important piece of the immuno-oncology puzzle, but it is not the only piece that connects cancer cells to the immune system. Identifying other immune molecules that interact with cancer cells is an important focus for researchers at the moment as they hope to find new pathways towards creating novel immunotherapy options for patients by “revving” up the their immune systems.
Similar to CTLA-4, PD-1 is another receptor molecule that is expressed on the surface of T cells. PD-1, which stands for Programmed Cell Death 1, serves as an immune checkpoint regulating the activation of T cells. Over the last two decades, researchers have found that PD-1 is also similar to CTLA-4 in that it acts as a regulator of T cell activation and, also similar to CTLA-4, can be co-opted by cancer cells to avoid an immune response. Interestingly though, the intracellular signaling mechanisms of the two receptors appear to be different, facilitating the development of multiple immunotherapies targeting these particular receptors.
Bristol-Meyers Squibb has developed a monoclonal antibody-based anti-CTLA-4 treatment called ipilimumab that targets metastatic melanoma, while another human antibody, tremelimumab, has been under clinical investigation and trials in humans. Merck has developed a PD-1 blocking compound known as pembrolizumab for treating advanced melanoma; Bristol-Meyers Squibb also developed a PD-1 monoclonal antibody called nivolumab that was approved in 2014 to treat metastatic melanoma. In addition to these antibodies targeting PD-1, several other PD-1-based therapies are now in development. It’s also interesting to note that both Bristol-Meyers Squibb and Astra Zenca have been actively exploring whether or not the use of combinations of CTLA-4 and PD-1 blocking therapies could prove more effective in treating certain forms of cancer.
Personalizing the Fight
Carl June is taking another approach to developing new immunotherapies. Rather than focusing on developing antibodies or other molecules to interact with receptors naturally expressed on the T cell surface such as CTLA-4 or PD-1, June and other researchers have turned to engineering T cells to make them more active against cancer cells.
June, who is a professor at the Perelman School of Medicine and director of Translational Research in the Abramson Cancer Center at the University of Pennsylvania, is working on what has become known as chimeric antigen receptor (CAR) therapy. This idea dates back to the late 1980s when Zelig Eshhar, an immunologist at the Weizmann Institute of Science in Tel Aviv, developed the first CAR T cells. Shortly after he published the method, Eshhar visited the United States to work with Steven Rosenberg at the National Institutes of Health, where together they genetically engineered a T cell with specific cancer cell–targeting single-chain antibody variable regions. They then demonstrated that the redirected T cells could specifically lyse a human ovarian carcinoma cell line. Since that time, the design and construction of a variety of engineered T cells has led to several potential immunotherapy applications, some of which are now in clinical trials.
June’s work on CAR T cells led to one of the first T cell therapy clinical trials, CTL019, for B cell cancers such as B cell non-Hodgkin lymphoma and acute lymphoblastic leukemia. The idea behind CTL019 is to generate patient-specific T cells modified to express a protein that recognizes and binds CD19 on cancerous B cells. The initial results from the clinical trial, published in The New England Journal of Medicine in 2014, were encouraging: 30 patients with leukemia were treated with CAR T cell therapy, 27 went into remission for some length of time, 19 experienced continued remission, and 7 experienced recurrence (3). “However, because so few patients have been treated, and because those patients have been followed for a relatively short time, it is critical that more adult and pediatric patients are enrolled in the study to determine whether a larger group of patients with B cell cancers will have the same response, and maintain that response,” noted a University of Pennsylvania webpage describing the clinical trial efforts. Still, for the size of the study, the result made quite a strong impression on the scientific community.
“The patients who participated in these trials had relapsed as many as 4 times, including 60 percent whose cancers came back even after stem cell transplants. Their cancers were so aggressive they had no treatment options left,” Stephan Grupp, professor of Pediatrics at the Perelman School of Medicine and director of Translational Research in the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia, as well as lead investigator on the CTL019 trial, said in a press release following the 2014 publication. “The durable responses we have observed with CTL019 therapy are unprecedented.”
CTL019 has now pushed into a Phase II clinical trial, and June and the University of Pennsylvania are partnering with Novartis Pharmaceuticals to continue trials. On the heels of the strong CTL019 results, other companies, included Pfizer and Amgen, have started partnerships with other investigators developing CAR T cell immunotherapies.
It’s worth noting that immunotherapy, even though years in the making, is still a very new field of research. In 2013, Science magazine announced cancer immunotherapy as their scientific “Breakthrough of the Year,” but in an article announcing the winner, Jennifer Couzin-Frankel noted that their decision to pick immunotherapy actually became a topic of internal debate amongst the staff. “In celebrating cancer immunotherapy—harnessing the immune system to battle tumors—did we risk hyping an approach whose ultimate impact remains unknown?”, Couzin-Frankel wrote in her news article. Ultimately, they concluded that it passed the test as a major scientific breakthrough. Looking back now, immunotherapy has come a good way in two years. Scientists working on immunotherapy are shaping the way in which cancer research and treatment is being thought about. The field continues to evolve, moving treatment in exciting new directions with each discovery and clinical trial—a breakthrough indeed.
Editors Note: BioTechniques will be hosting an immuno-oncology webinar on October 6, 2015. Find out more...
References
1. Brunet, J.F. et al. 1987. “A new member of the immunoglobulin superfamily – CTLA-4” Nature. 328(6127):267-270.
2. Leach D.R., Krummel, M.F., and Allison, J.P. 1996. “Enhancement of antitumor immunity by CTLA-4 blockade” Science. 271(5256):1734-6.
3. Maude S.L. et al. 2014. “Chimeric antigen receptor T cells for sustained remissions in leukemia” N Engl J Med. 371(16):1507-17.