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 two weeks, we’ll provide some background and context for these advancements.
This week we're highlighting breakthroughs in the anti-tumor capabilities of T cells, macrophages, and natural killer cells. For more on cancer immunotherapy and our 30 Days of CRI Impact, be sure to follow #CIM18 on Twitter.
2002: Dr. Cassian Yee
The T cells of our immune system are extremely powerful when it comes to fighting tumors. While they are capable of recognizing and eliminating cancer cells naturally, sometimes they need a little help. In this groundbreaking work funded by CRI at the Fred Hutchinson Cancer Research Center, Dr. Cassian Yee showed for the first time that the immune cells of melanoma patients could be removed, enhanced in the lab, and then used to help fight their disease. After obtaining immune cells from the blood of these patients, the cells were exposed to two antigens—MART1/MelanA and gp100, commonly expressed by melanoma cells—and then expanded to increase their numbers. Following re-infusion into the patients, these cells then sought out and attacked their tumors, resulting in responses or at least stabilization in 8 of the 10 patients treated. This initial proof of principle subsequently led to a number of adoptive T cell immunotherapy approaches that involve taking patients’ T cells and turning them into superior cancer-fighters before giving them back to patients. One of the most noteworthy strategies that was built on this breakthrough is CAR T cell therapy, which involves equipping patient-derived T cells with specialized receptors that enable them to more effectively target and eliminate cancer cells. Two CAR T cell immunotherapies have already been approved by the FDA for treatment of leukemia and lymphoma.
2003: Drs. E. John Wherry, David Masopust, and Rafi Ahmed
Not all “killer” T cells are created equal in terms of their power or their persistence, and Drs. E. John Wherry, David Masopust, and Rafi Ahmed of Emory University demonstrated that a subset called central memory T cells are particularly effective at fighting disease. That same year, Wherry and Ahmed also showed that the killer T cells that give rise to these long-lived central memory T cells could be identified by their increased expression of the interleukin-7 receptor. While the team’s initial CRI-funded work in 2003 revealed the importance of these cells in the context of viral infection, since then these memory T cells have been shown to play an important role in cancer too, and their formation and presence has been associated with improved immunotherapy benefits. Most recently, cell-based immunotherapy approaches such as CAR T cell therapy have also incorporated this crucial subset of killer T cells and are now being evaluated in clinical trials.
2014: Dr. Michel Sadelain
CAR T cells—genetically modified immune cells referred to as “living drugs”—have revolutionized treatment for blood cancers like leukemia and lymphoma, but they haven’t yet been as successful against solid tumors such as breast cancer, lung cancer, or pancreatic cancer. In the cases of leukemia, where cancer cells circulate in the blood, or lymphoma, where cancer cells form in the lymph nodes that are part of the immune system, it’s much easier for CAR T cells to engage and eliminate the cancer cells. On the other hand, with solid tumors, CAR T cells must exit circulation and navigate their way through sometimes dense tissue within organs to reach cancer cells, among other hurdles. One potential way to address this challenge was demonstrated by Memorial Sloan Kettering Cancer Center’s Dr. Michel Sadelain, who showed in mice that regional delivery of CAR T cells—into the pleural space surrounding the lungs rather than through an IV into the blood—resulted in increased activation of CAR T cells as well as enhanced anti-tumor activity and persistence against mesothelioma, a cancer that arises in the lining of the lung. Subsequently, regional delivery of CAR T cells was also shown to improve the effectiveness of this approach in patients with cancer that had spread to the brain, and could potentially be applied in a number of other cancer settings as well.
2003: Drs. Jason Fontenot and Alexander Rudensky
Beyond “killer” T cells, there are several other types of immune cells that can influence immune responses against tumors. One is regulatory T cells (Tregs). In a major discovery made at the University of Washington, Drs. Jason Fontenot and Alexander Rudensky revealed that FOXP3 is the master molecular switch that controls the formation and continued activity of Tregs, and that its expression is crucial in preventing potentially lethal autoimmune responses. Despite the beneficial role that Tregs play in preventing autoimmunity, in the case of cancer their protective capabilities can backfire and cause them to protect tumors from immune responses. In fact, the effectiveness of the first checkpoint immunotherapy—the CTLA-4-blocking ipilimumab, which was approved for advanced melanoma in 2011—has been shown to depend on the elimination of Tregs within the tumor microenvironment.
2018: Dr. Susan Kaech
“Hot” tumors that have been recognized and infiltrated by T cells are much more likely to respond to checkpoint immunotherapy, while “cold” tumors are usually resistant to immunotherapy. As a result, there is a great need for strategies that can help the immune system better eliminate these “cold” tumors that comprise the majority of cancer cases. This year while at Yale University, CRI investigator Dr. Susan Kaech revealed one potentially promising approach that involved targeting macrophages, another type of immune cell, via the CD40 and CSF-1R pathways. This dual treatment that activated the CD40 pathway and inhibited CSF-1R was able to decrease the numbers of immunosuppressive macrophages and increase the numbers of anti-tumor inflammatory macrophages, which in turn was able to convert “cold” tumors into “hot” ones, enhancing T cell activity and tumor elimination. This approach could also potentially be combined with checkpoint immunotherapy to even further improve T cells’ ability to attack cancer cells.
2017: Drs. Roy Maute and Irving Weissman
One of the special abilities of macrophages, a type of immune system cell, is that they can literally eat damaged or diseased cells through a process called phagocytosis. Normal cells express certain markers that let macrophages know not to eat them, but unfortunately cancer cells can trick macrophages by taking advantage of these markers, too. While it’s been known that cancer cells can use the CD47 to protect themselves from being engulfed by macrophages, this CRI-funded work by Drs. Roy Maute and Irving Weissman of Stanford University revealed that the β2-microglobulin component of the MHC1 complex can be exploited by cancer cells for the same purpose. Furthermore, they showed that disrupting the interaction between MHC1 (on cancer cells) and LILRB1 (on macrophages) was able to enhance macrophage-mediated phagocytosis and enable more effective elimination of cancer cells. Like Dr. Kaech’s strategy above, this macrophage-targeting approach also has promising potential in combination with existing immunotherapy approaches that enhance the anti-cancer activity of T cells.
2006: Drs. Yoshihiro Hayakawa and Mark Smyth
Macrophages and “killer” T cells aren’t the only immune cells that can play a role in eliminating tumors—natural killer (NK) cells can, too. In this CRI-funded work, Drs. Yoshihiro Hayakawa and Mark Smyth of the Peter MacCallum Cancer Centre in Australia showed that NK cells were able protect against tumor formation in mice via interactions involving the NKG2D receptor pathway. Under the “stress” of infection or cancer, diseased cells, including some cancer cells, begin to express proteins on their surface that are recognized and bound by the NKG2D pathway, which then stimulates NK cells to attack. As a result of this breakthrough in our understanding of NK cells’ tumor-fighting capabilities, several immunotherapy strategies have been developed to take advantage of this pathway’s anti-tumor potential, including some CAR T cells that have been engineered to express the NKG2D receptor.
For more on cancer immunotherapy and our 30 Days of CRI Impact, be sure to follow #CIM18 on Twitter.