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30 Days of CRI Impact: Breakthroughs 1-9

June 09, 2018

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 funding from CRI. Here's some background on nine advancements and be sure to follow #CIM18 on Twitter for new updates.

1976: Drs. Hiroshi Shiku, Herbert Oettgen, and Lloyd Old

1976 Drs. Hiroshi Shiku, Herbert Oettgen, and Lloyd J. Old  Characterized natural anti-tumor immune responses in cancer patients

In the 1970s, few believed that the immune system had any protective power against cancer. Fortunately, this early CRI-funded work of Drs. Hirsohi Shiku, Herbert Oettegen, and Lloyd J. Old—the Father of Modern Tumor Immunology—helped show that the immune system does indeed play a role in our body’s efforts to protect us against cancer. In this case, these scientists, all at Memorial Sloan Kettering Cancer Center at the time, showed that melanoma patients had antibodies in their blood that recognized and reacted against antigens on their melanoma cells, which they were also able to characterize. This was one of the first key pieces of evidence that the immune system could precisely target cancer cells and launch responses against them, and helped establish the conceptual foundation of cancer immunology and immunotherapy.

1979: Drs. John Pesando and Stuart Schlossman

1979 Drs. John Pesando and Stuart Schlossman  Shed light on an important marker associated with T cells

As we saw above, antibodies produced by our immune cells enable the immune system to naturally target cancer, but antibodies can also be used for a variety of other purposes. During the 1970s, major advances in antibody production were made, which granted scientists the ability to customize targeted antibodies for a variety of applications and enabled these precision-targeting proteins to be used for the study of many different biological processes, especially in the still relatively nascent field of immunology. In this CRI-funded work, Drs. John Pesando and Stuart Schlossman of the Fred Hutchinson Cancer Research Center created antibodies that targeted the 1a antigens found on activated human T cells and enabled them to characterize these important markers in the context of T cell biology. (During the same year they also developed, with the help of CRI funding, other customized antibodies that could target specific antigens on leukemia cells.)

1981: Drs. Wolfgang Dippold and Lloyd J. Old

1981 Drs. Wolfgang Dippold and Lloyd J. Old  Created an antibody that can detect p53 that’s been useful in studying this important tumor suppressor protein

In the context of the lab, antibodies can also be used to study the intracellular components of cells. With the aid of CRI funding, Drs. Wolfgang Dippold and Lloyd J. Old of Memorial Sloan Kettering Cancer Center developed an antibody to detect p53, an important tumor suppressor protein whose job is to prevent cells from excessive and inappropriate proliferation. We now know that p53 is often mutated, and its growth control disabled, in a wide variety of malignant cancers, thus allowing for their unconstrained growth. At the time, all that was known about this important protein was that it was present in a variety of cancer types. In addition to the development of this p53-targeting antibody, one of the most important contributions of this CRI-funded work was to show that p53 resided in the nucleus of cells, where it exerts its control over cell growth.

1983: Dr. Susumu Tonegawa

1983 Dr. Susumu Tonegawa  Discovered how the immune system can create trillions of customized antibodies

By now, you might be wondering just how our immune system is able to create all these different antibodies that can target such diverse cellular markers. Well, in the late 1970s and early 1980s, Dr. Susumu Tonegawa of the Massachusetts Institute of Technology, deciphered this mystery with support from CRI, and in 1983 he revealed the solution to this riddle. The B cells of our immune system possess the genes to produce a wide variety of antibodies from the get go, but what they do as they mature is utterly remarkable—they can literally rearrange and recombine the DNA that encodes the different antibody components, and by doing so, they can tinker with the design of antibodies. Through this process, the B cells of the immune system can collectively manufacture trillions of different types of antibodies, ensuring that they can target an almost limitless variety of threats, including tumors. For this discovery, Dr. Tonegawa was awarded the 1987 Nobel Prize in Physiology or Medicine.

2000: Drs. Terri Towers and Jeffrey Ravetch

2000 Drs. Terris Towers and Jeffrey Ravetch  Revealed that the antitumor activity of antibodies depends upon the types of FcR receptors the antibodies bind to

While the “front ends” (targeting, or variable regions) of antibodies that bind to the surface of threats—viruses, bacteria, or cancer—are often considered the most important components of antibodies, Drs. Terri Towers and Jeffrey Ravetch of The Rockefeller University showed that the “back ends” (or constant regions) are also important for the anti-tumor activity of targeted antibodies. Once an antibody’s “front end” binds the target, its “back end” can bind to Fc receptors (FcRs) on other immune cells that pass by and tell them how they should react to the antibody-bound entity. In the context of cancer cells that are bound by antibodies, this CRI-funded work showed that antibodies’ back ends must engage activating FcRs in order to promote the destruction of cancer cells through a process known as antibody-dependent cellular cytotoxicity, or ADCC. This insight has allowed us to improve the anti-cancer activity of targeted antibodies, for which there are more than 20 currently approved to treat cancer. More recently, Ravetch and CRI postdoctoral fellow Dr. Rony Dahan have revealed the importance of antibody-FcR binding in checkpoint immunotherapy as well.

1987: Drs. Marcia Blackman and Philippa Marrack

1987 Drs. Marcia Blackman and Philippa Marrack  Identified and isolated the portion of the T cell receptor that binds to MHCII proteins

Our first few facts focused primarily on the antibodies produced by B cells. Now, we’ll turn our attention to perhaps the most important “soldiers” in the immune system: T cells. While B cells produce “homing missiles” in the form of antibodies that seek out threats to bind to, T cells go out and engage threats directly, specifically with their T cell receptors (TCRs). In a way, the mystery of the TCR took longer to unravel than that of the antibody, given that TCRs remain attached to, and influence the activity of, living cells. Whereas antibodies are capable of binding molecules—any molecules, really—directly on cells, the TCRs of T cells must interact with their specific target in the context of the major histocompatibility complexes (MHCs), which present the targets (known as antigens) to T cells. There are two types of MHCs, class I and class II, and both play important roles in educating T cells about what threats look like and enabling them to target and destroy them. These TCR-MHC interactions lie at the heart of our powerful adaptive immune responses, and while there were many CRI-funded projects that helped elucidate its complexity, we chose this breakthrough by Drs. Marcia Blackman and Philippa Marrack of the University of Colorado and the National Jewish Medical and Research Center because it revealed exactly which components of the TCR and the class II MHC bound to each other to promote activity of helper (CD4+) T cells. This breakthrough was an important contribution that helped pave the way for many of the T cell immunotherapies that are in the clinic today.

1983: Drs. Jonathan Austyn and Ralph Steinman

1983 Drs. Jonathan Austyn and Ralph Steinman  Demonstrated that dendritic cells promote T cell growth and adaptive immune responses

Another group of immune cells that play crucial roles in adaptive immune responses are dendritic cells, named for their “dendritic” or “tree-like” arms that enable them to reach out and interact with a variety of other immune cells. While dendritic cells don’t attack tumors directly, they play a central role in coordinating overall immune responses by educating T cells about what cancer cells look like so that they can go destroy them. A foremost pioneer in this field, Dr. Ralph Steinman discovered dendritic cells (a breakthrough for which he would be posthumously awarded the 2011 Nobel Prize in Physiology or Medicine) and went on to characterize many aspects of their behavior, and in this CRI-funded work he revealed their ability to promote T cell growth and stimulate adaptive immune responses. Due to this important activity, dendritic cells have already been incorporated into one FDA-approved immunotherapy as well as several others that are currently being evaluated in clinical trials.

2001: Drs. Vijay Shankaran, Allen Bruce, Hiroki Ikeda, and Robert Schreiber

2001 Drs. Vijay Shankaran, Allen Bruce, Hiroki Ikeda, and Robert Schreiber  Discovered and described the phenomenon of “cancer immunoediting”

In the 1970s, an experiment was performed that appeared to end the debate once and for all—“proving” that the immune system doesn’t protect us against cancer. Fortunately, Dr. Robert Schreiber, who had just finished his Ph.D., wasn’t entirely convinced. Several decades later in the late 1990s, he and the members of his lab revealed that not only does the immune system naturally protect against the formation of tumors through a process known as immunosurveillance, but also that the relationship between cancer and the immune system is much more complicated than almost anyone appreciated. Through a process called “immunoediting”—which he discovered, described, and coined—he demonstrated in mice that as the immune system destroys some tumor cells, it can also sculpt, or edit, the remaining population of tumor cells into a form that enables them to evade the immune system’s detection. By teaching us these “rules of the game,” in the words of Dr. Antoni Ribas (see below) Dr. Schreiber and his colleagues greatly expanded our understanding of the relationship between cancer and the immune system. Because this discovery was far ahead of its time, its implications took a while for many in the field to wrap their heads around, but fortunately these insights were later validated in human cancer patients and are now being used to develop more effective cancer treatments in the clinic, most especially through the recognition of ways in which cancer can escape immune responses and develop resistance against immunotherapy.

2014: Dr. Antoni Ribas

2014 Dr. Antoni Ribas  Identified patient traits that could predict responses to checkpoint immunotherapy

Ultimately, over the past 65 years, CRI’s investments in research to better understand the relationship between cancer and the immune system were all done with one singular goal in mind: to harness the immune system’s power to cure cancer in human patients. With the approval of the first checkpoint immunotherapy in 2011, followed by two others in 2014, those dreams have begun to be realized in a significant way. However, these were by no means cures—at least not for the vast majority of patients—and so we continued to recognize the need for basic research that enables us to learn more and more about cancer and the immune system and how specific immunotherapies work so that we can maximize their benefits for patients. To that end, the work of UCLA’s Dr. Antoni Ribas, a member of the CRI-SU2C Immunology Dream Team, provided extremely important insights into why certain patients benefited from immunotherapy while others didn’t. In the context of treating melanoma patients with pembrolizumab, an anti-PD-1 checkpoint inhibitor, Dr. Ribas’ team revealed that patients whose tumors had already been recognized and infiltrated by “killer” T cells were much more likely to respond to this checkpoint immunotherapy approach. This was one of the first big advances in understanding what enables immunotherapy-treated patients to be successful. Now, because of this CRI-funded work, doctors have a way to determine which patients are most likely to benefit from immunotherapy and can use this information to guide their treatment decisions accordingly.

*Immunotherapy results may vary from patient to patient.

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