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I skimmed an article on a recent experiment which suggested that it was effective to inject induced colon cancer tumors with an attenuated salmonella variant. According to the article, this stimulated an immune response which suppressed metastasis of the cancer. How exactly does this work?
Tumors are commonly infiltrated with lymphocytes, including T cells, macs, DCs and B cells. The crux of the paper is that their attenuated virus secretes TLR ligands (Toll-like receptor) that resulted in an activation of tumor-suppressive M1 macrophages, a concomitant reduction in immune-suppressive M2 macrophage activity, and an influx of immune infiltrate to the tumor.
So M1 macs are activated typically by IFN-y and LPS stimulation, which is typically through TLR4. Their salmonella is attenuated and causes no disease, check one. It's gram-negative and thus has LPS, check two. It's engineered to secrete bacterial flagellin, a TLR5 agonist, check three.
M1 macs secrete IL12, important for polarizing T cells to TH1/TC1 phenotypes that are oncolytic, and IL10 which can elicit anti-tumor immunity though it's reputation is that of an immunosuppressant. M1 macs can also kill tumors of their own accord by producing nitric oxide which is cytotoxic to tumor cells. TLR4 agonsim on it's own accord also activates T cells in an NF-kB-dependent manner.
Whats also interesting is the inflammatory signal actuated by the macrophages actually tells other immune cells "hey come check this out," and potentially makes for a more robust anti-tumor response. The idea is that inflamed tissues secrete signalling or chemotactic molecules called chemokines which are picked up by chemokine receptors on leukocytes, telling them to enter the zone of infection (and thus the malignancy).
You'll also find, however, that despite immunological advances, modulating cells is a challenge due to the nature of each type of cancer's TME (tumor microenvironment). And so in your paper they tested it in a murine system in bladder cancer, but will it work in a human melanoma must be qualified, for example.
This year, the Nobel Prize in Physiology or Medicine was given to James P. Allison and Tasuku Honjo- “for their discovery of cancer therapy by inhibition of negative immune regulation”. The era of cancer immunotherapy has come, offering a beacon of hope in our long, ongoing fight against this serious disease. Increased knowledge of the human immune system has been translated into exciting clinical solutions not only in cancer, but other disease areas as well. The objective of this interactive session on Translational Immunology is to provide a comprehensive overview of the immunotherapy landscape and to highlight successful immune modulation approaches in various diseases areas, such as cancer, autoimmune diseases and infectious diseases.
The event started with a talk given by Prof. Toh Han Chong (NCCS, Duke-NUS, Tessa Therapeutics). He shared with us the important discoveries in the history of immunology dating back from the 90s until now. To him, the recent breakthroughs in immunology were made by standing on the shoulders of giants, building on the discoveries of brilliant scientists likeSir Gregory Winter andAlexander Fleming.Prof. Toh gave an interesting analogy that the fetus, which is foreign from the mother’s perspective, does not provoke an immune reaction from the mother, in a very similar way that cancer avoids the immune system. Thus, a better understanding of the immune mechanisms during pregnancy can improve our understanding of cancer immunology. An in-depth understanding of cancer immunology and cancer mutations with the advancements in genomics will help bring in the new dawn for cancer therapy.
Prof. Toh sharing stories about key milestones in immunology research history.
Following Prof. Toh’s talk, a panel discussion with distinguished panelists consisting of Prof. Toh, Prof. Salvatore Albani (Eureka Instititue of Translational Medicine, Translational Immunology Institute), Dr Piers Ingram (Hummingbird Bioscience), and Prof. Ooi Eng Eong (Duke-NUS, Tychan) was then convened with the floor open to questions from audience members. The Q&A generated a vibrant discussion on the upcoming exciting developments and challenges we can expect in this new era of immunotherapy.
Here are some highlights from the Q&A session:
It is an exciting era in Singapore for immunology. Besides the limited funding available, what is missing in Singapore for translational immunotherapy?
Dr. Albani: The tendency to be reactive rather than proactive may be the biggest hurdle for translational immunotherapy in Singapore. Though the ability to react quickly in Singapore may allow us to compete in this field, we might not be able to lead, especially in areas where innovation is crucial, if we are unwilling to take risks. The willingness to take risks is paramount to be the innovative leader in this field.
Dr. Ingram: Only the accumulation of experience from multiple cycles of trials and failures will allow us to achieve success. We need the patience and willingness to build an ecosystem because there is no quick way to do it.
Dr. Ooi: The appetite for risk in Singapore is still lower than that in Boston and Silicon Valley. It is hard to convince people who are risk averse and impatient to invest in translational immunology, where the fruits of labor will only be apparent after a significant number of years. In Singapore, there is a greater focus on Medtech rather than biotech because it is faster for Medtech startups to achieve commercial success. We might really need to tough it out in order to win big.
Prof. Toh: One advantage of Singapore is that it can connect the important dots and gather all strength together. But in certain areas Singapore might need to do more. For instance, to encourage biotechnology innovation and build a more sustainable ecosystem, Singapore needs to work hard to catch up with regions like Boston and Cambridge.
What are the considerations of a big (biotech) company for coming to Singapore or leaving Singapore?
Dr. Albani: Singapore is doing so much as compared to some much larger countries in various aspects to build its ecosystem and lead the way. So if you do want to make a difference in improving patient health, that is a reason to stay in Singapore and there are plenty of opportunities here.
Prof. Toh: Singapore has been great in some ways but compared to Massachusetts, Singapore is not yet an epicenter. Compared to places like Silicon Valley, the tolerance of failure in Singapore is not high enough. We will need to accept failure to achieve more success.
Dr. Ooi: Certain diseases have mutations that are prevalent in Asia. The fact that Singapore is in Asia gives us certain advantages to tackle prevalent diseases in the region. For example, Singapore has significant influence in regional organizations such as Association of Southeast Asian Nations (ASEAN) and this could improve the capability of Singapore in accessing this regional market. Another example is that if the drug needs to go through clinical trials in major Asian populations, such as Chinese, Indians or Malaysians in order to get its approval, Singapore then possesses the right data to access those markets as a result of its own population composition.
Dr. Ingram: One advantage Singapore has in creating an ecosystem is the presence of big pharma companies here.
Dr. Ooi addressing questions raised by the audience during the panel discussion
What might be the next “big” instructive technology in the next 5 years in immune oncology?
Dr. Albani: (1) The biggest challenge now is to think out of the box and look at immunology systematically. The next big technologies are those that can explore both upstream, and downstream in research innovation. They should not be just mere tools, but technologies that enable understanding and manipulating at the interfaces of immune system and tissues. (2) The utilization of precision medicine, to target a small proportion of patients based on their genomic or molecular profiles is our current “low-hanging fruit”. In this area, we see many opportunities.
Dr. Ooi: One fundamental problem of the current healthcare situation is how to make medicine more accessible and affordable. Research that can reform the regulatory system may be what the society truly needs.
Prof. Toh: People making breakthroughs did not search for trendy topics to work on. In the end, we still need to go back to ask fundamental questions for research, which I believe will contribute to the next “big” technology. However, I do believe in the diverse pool of available technologies and innovations, predictive public health would be worth exploring. It will play an important role in the future healthcare system, where the identification of population to intervene is crucial in catching high risk patients even before they develop the disease.
Dr. Ingram: It is crucial to consider questions regarding “when to use the right drugs at the right time”. Technologies that can help close this gap will be very promising.
The event ended with an active networking session among speakers and participants. The BCS team would like to thank all speakers and participants for making it a successful interactive event!
Types of Cancer Immunotherapy Can Treat
Through ongoing research, we’re learning more about how the immune system interacts with cancer and using that information to develop new ways of treating the disease. Immunotherapy is currently used to treat the following cancers:
- Bladder cancer
- Bone marrow disorders
- Brain cancer
- Breast cancer
- Colorectal cancer
- Multiple Myeloma
- Head and neck cancers
- Kidney cancer
- Lung cancer
- Ovarian cancer
- Prostate cancer
- Synovial Cell Sarcoma
- Stomach Cancer
The Application of Natural Killer Cell Immunotherapy for the Treatment of Cancer
Natural killer (NK) cells are essential components of the innate immune system and play a critical role in host immunity against cancer. Recent progress in our understanding of NK cell immunobiology has paved the way for novel NK cell-based therapeutic strategies for the treatment of cancer. In this review, we will focus on recent advances in the field of NK cell immunotherapy, including augmentation of antibody-dependent cellular cytotoxicity, manipulation of receptor-mediated activation, and adoptive immunotherapy with ex vivo-expanded, chimeric antigen receptor (CAR)-engineered, or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack non-hematopoietic tissues, suggesting that an NK-mediated antitumor effect can be achieved in the absence of graft-vs.-host disease. Despite reports of clinical efficacy, a number of factors limit the application of NK cell immunotherapy for the treatment of cancer, such as the failure of infused NK cells to expand and persist in vivo. Therefore, efforts to enhance the therapeutic benefit of NK cell-based immunotherapy by developing strategies to manipulate the NK cell product, host factors, and tumor targets are the subject of intense research. In the preclinical setting, genetic engineering of NK cells to express CARs to redirect their antitumor specificity has shown significant promise. Given the short lifespan and potent cytolytic function of mature NK cells, they are attractive candidate effector cells to express CARs for adoptive immunotherapies. Another innovative approach to redirect NK cytotoxicity towards tumor cells is to create either bispecific or trispecific antibodies, thus augmenting cytotoxicity against tumor-associated antigens. These are exciting times for the study of NK cells with recent advances in the field of NK cell biology and translational research, it is likely that NK cell immunotherapy will move to the forefront of cancer immunotherapy over the next few years.
Keywords: ADCC CAR NK cells NK-92 adoptive immunotherapy anti-KIR antibody natural killer cells transplantation.
One of ISB's strong values is communicating science to public. This meeting was no exception much of it was recorded and the video's are posted on the ISB YouTube channel.
The first day focused on immunotherapy. Digital World Biology has a keen interest in immunotherapy because it is a major area of employment that needs many technicians and is a driver for our collaboration with Shoreline Community College in developing an immuno-bioinformatics course. To learn more about companies working in immunology and immunotherapy check out the listing of immunology companies on Biotech-Careers.org
An immunoproteosome colored by
secondary structure in Molecule World™
Dr. Phil Greenberg (head of immunology at the Fred Hutch) kicked off the first session. Much of his talk focused on the reasons why T cell therapies do not always work in fighting cancer and how we can improve immunotherapy for solid tumors. While immunotherapy has shown great promise, it is not a panacea. A large number of patients still do not respond and these therapies thus far have worked best for blood-based cancers (aka leukemia). Using single cell RNA-Seq (scRNA-Seq) the Greenberg lab has identified several reasons why immunotherapies fail. First, T cells die, which limits their ability to expand. Second, tumors suppress T cell growth. Some of this suppression is related to a lack of CD8 (T cell) activation.
Dr. Wei Zhang (Wake Forest School of Medicine) shared a doctors' perspective. His lab focuses on using genomic methods to understand glioma - a deadly form of brain cancer. Through his talk, we were reminded of the challenges in precision oncology from extreme tumor heterogeneity, to expensive treatments that offer too little life extension, to physician fatigue.
On an optimistic note, Dr. Zhang shared results from mining TCGA (The Cancer Genome Atlas) data to find that mutations in CTNNB1 (Catenin Beta 1) can predict cancer outcomes. CTNNB1 encodes a protein that is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. CTNNB1 is also an oncogene, which makes sense given its role in cell growth.
Zhang also discussed findings from liquid biopsy work that show a high prevalence of TP53 mutations in African Americans, and conjectured that this may be correlated with higher rates of smoking menthol cigarettes. As to the physician fatigue, Zahng made the point that a challenge in precision oncology, where DNA sequencing is used to define treatments, is that physicians have not yet been trained to interpret the data. The full talk was captured in the ISB videos.
Dr. Lili Yang (Molecular Biology Institute, Los Angeles) presented work on invariant natural killer T cells (iNKT cells). These are the special forces of the immune system and are rare. If we look at the cells in a single drop of blood, we find only 10 iNKT cells, 10 million red blood cells, 100,000 white blood cells and 5000 conventional T cells. The invariant in iNKT cells is because they also contain a specific T cell receptor (TCR) rearrangement (Vα24Jα18).
The iNKTCR recognizes lipid antigens on CD1d (an MHC class I like molecule, that is NOT polymorphic), so they can target multiple types of cancer (by recognizing tumor-derived glycolipids) using multiple mechanisms that are independent of protein tumor antigen and MHC restrictions. Thus, they can be a powerful immunotherapy if they are present in a high enough concentration. Thus, Dr. Yang's research group is working on ways to increase iNKT cells in cancer by feeding in alpha galacto-ceramide, or trying to expand iNKT cells in vitro and transfuse back into patients, or engineer hematopoietic stem cells to develop into iNKT cells. In the stem cell engineering approach, Yang's lab has had success by adding a transgene that over expresses the Vα24Jα18 TCR. The over expression blocks normal TCR rearrangement and many iNKT cells can be grown and infused back into the patient. So far, this has only been tested in mice, but they are learning the details about production and managing iNKT cell growth.
For more on iNKT cells checkout Discovery of NKT cells and development of NKT cell-targeted anti-tumor immunotherapy for history and background and the video of Dr. Yang's talk.
Other talks by Dr. Bernard Fox (UbiVac) continued the theme of cancer immunotherapy. Fox, CEO of UbiVac and the Harder Family Chair for Cancer Research, at the Earle A Chiles Research Institute, Providence Portland Cancer Center, discussed work in understanding how cell surface markers can be used as biomarkers in defining how immunotherapies are used. While very effective at killing cancer cells, immunotherapies can also kill patients by stimulating the release of cytokines that further stimulate killer T cell growth. His teams are exploring how to identify cell surface markers in conventional blood tests, and also by looking at tumor sections under microscopes because their data indicate that spacial relationships between markers on cells can also matter. To learn more check out the video of Dr. Fox's presentation.
Dr. Alex Fanzusoff (CEO PACT Pharma) closed the session on immunotherapy. PACT Pharma develops immunotherapies that target neoantigens. Neoantigens (new antigens) have always been present and for a long time and have been speculated to be a driver in how the immune system plays a role in preventing cancer. The concept of neoantigens as potential targets of immunotherapy did not fully develop until high throughput DNA sequencing systems became available and large surveys of cancer mutations could be studied. Dr. Fanzusoff shared PACT Pharma's methods for mapping T cell / neoantigen recognition. Their experiments utilize microfluidic devices that mix T cells with nanoparticles containing DNA barcode sequences with fluorescent molecules. The system captures T cells that bind tumor specific neoantigens, and their machine learning algorithms then determine which T cells are involved in interactions will have the greatest therapeutic benefit for further engineering and reintroduction into patients.
Posted from Discovering Biology in a Digital World by Todd Smith on Fri May 03, 2019
Post-translational regulations of PD-L1 and PD-1: Mechanisms and opportunities for combined immunotherapy
Antibodies targeting programmed cell death protein 1 (PD-1) or its ligand programmed death-ligand 1 (PD-L1) are profoundly changing the methods to treat cancers with long-term clinical benefits. Unlike conventional methods that directly target tumor cells, PD-1/PD-L1 blockade exerts anti-tumor effects largely through reactivating or normalizing cytotoxic T lymphocyte in the tumor microenvironment to combat cancer cells. However, only a small fraction of cancer patients responds well to PD-1/PD-L1 blockade and clinical outcomes have reached a bottleneck without substantial advances. Therefore, better understanding the molecular mechanisms underlying how PD-1/PD-L1 expression is regulated will provide new insights to improve the efficacy of current anti-PD-1/PD-L1 therapy. Here, we provide an update of current progress of PD-L1 and PD-1 post-translational regulations and highlight the mechanism-based combination therapy strategies for a better treatment of human cancer.
Meet the Director of Cleveland Clinic’s new Center for Immunotherapy and Precision Immuno-Oncology
Cleveland Clinic’s new Center for Immunotherapy and Precision Immuno-Oncology, directed by renowned cancer researcher Timothy Chan, MD, PhD, plans to unite researchers in multiple disciplines to advance personalized cancer care and develop novel immune system-based treatments.
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“In the last seven or eight years, immunotherapy has arisen as one of the main pillars of cancer therapy,” says Dr. Chan, who joined Cleveland Clinic in April 2020 from Memorial Sloan Kettering Cancer Center and Weill Cornell School of Medicine. “Moreover, new immunotherapy agents are transforming other types of care, such as for autoimmune disorders and infectious disease.
“Our new center resides in both the research and the therapeutic realms,” he says. “The plan is to build a state-of-the-art, enterprise-level organization to discover, as well as to bring into the clinic, new immunotherapies. We’re focusing on big data — on experimental therapeutics, driven by genomic analysis and high-throughput immunoprofiling — and we’re leveraging all the strengths of the Cleveland Clinic enterprise to do this. I’m ecstatic to be here.”
“Innovation in precision immunotherapy is one of the most exciting areas in cancer research,” says Taussig Cancer Institute Chairman Brian J. Bolwell, MD. “The addition of Dr. Chan and the new center’s focus on research and clinical trials will strengthen our ability to provide advanced treatment options for our patients.”
Dr. Chan is an international expert in precision immuno-oncology and a pioneer in using genomics to determine patients’ response to immunotherapies. His lab at Memorial Sloan Kettering (MSK) made foundational discoveries, including the finding that immune checkpoint inhibitors ultimately target somatic mutations. This has led to a global effort to understand and use neoantigens in cancer therapies. It also spurred the development of a new generation of cancer vaccines aimed at unleashing the immune system against mutations in tumors. At MSK, he ran a successful cooperative center, the Immunogenomics and Precision Oncology Platform, that propelled translational immunology research and trial work.
Dr. Chan has published more than 200 peer-reviewed articles and has made landmark discoveries in his field, such as how immune checkpoint therapies work in patients, how immunotherapies alter tumors during treatment, and how individual genes enable certain patients to benefit more from immunotherapy. He has received numerous awards, including the National Cancer Institute Outstanding Investigator Award in 2018.
In addition to directing the new center, Dr. Chan will hold staff positions in the Lerner Research Institute’s Genomic Medicine Institute and the Taussig Cancer Institute’s Department of Radiation Oncology. He joins the leadership of the National Center for Regenerative Medicine at Case Western Reserve University as Co-Director, with Stanton Gerson, MD. Dr. Chan also will collaborate with experts in Cleveland Clinic’s new Center for Global and Emerging Pathogens Research, which is focused on broadening understanding of immunology and microbial pathogenesis with the goal of improving treatment for a variety of diseases, including virus-induced cancers.
He earned his MD and PhD in genetics from Johns Hopkins University, where he completed a residency in radiation oncology and a postdoctoral fellowship in tumor biology. He is board-certified in radiation oncology and is an elected member of the Association of American Physicians.
In a wide-ranging conversation with Consult QD, Dr. Chan discusses his research, immunotherapy’s progress and potential, and his goals for the new center.
How did you become interested in cancer genomics and immuno-oncology?
Dr. Chan: At Johns Hopkins, where I did my MD/PhD work, I trained as a cancer geneticist, with Bert Vogelstein and others. Even though it wasn’t fully appreciated yet that the immune system plays a major role in facilitating treatment response as well as control of tumors, there was still a lot of research by people I knew there that really piqued my interest, including Drew Pardoll and Lieping Chen, whose work has really revolutionized the field of immunotherapy.
When I moved to Memorial Sloan Kettering, Jim Allison, whose lab was upstairs, and others had been developing the concept of immune checkpoint blockade. Back then, nobody had any idea that cancer genetics was linked to immunotherapy. Ipilimumab, one of the first foundational immune checkpoint blockade agents, had just come on the scene. There was a lot of skepticism about the whole concept. It was thought that there was something wrong with the immune cells themselves. Our group worked with investigators developing the first immune checkpoint agents and formulated a collaboration to try to understand how immunotherapy works, and how to use this knowledge to develop new and better therapies.
The first discovery that came from our group was that it was really the cancer-specific mutations that the immune system saw and targeted when a patient got the drug to reawaken the immune system. The mutations necessary for cancer cells to proliferate cause the cancer cells themselves to appear foreign. And that’s what the immune system is all about — identifying what is foreign to the body and eliminating it. So that was a fundamental link. The mutations themselves are the targets for immunotherapy. Therefore, the more mutations a tumor has, the better one does. This concept has become fundamental in the field and contributed to the first pan-cancer FDA approval of a drug: the approval of anti-PD1 for mismatch repair-deficient tumors.
That concept seems so basic now.
Dr. Chan: It was highly controversial at the time. It took a while for people to get comfortable with the idea.
The idea that cancer varies from individual to individual?
Dr. Chan: That, and that the mutation profile itself was determining the response of immunotherapy agents. I’m particularly proud that this concept has led to worldwide efforts to find smarter and better targets for cell therapy, CAR T-cells, vaccines, all sorts of things. A very good friend of mine, Luis Diaz, ran a clinical trial that showed that cancers with high mutation burdens due to mismatch repair deficiencies responded well to immunotherapy. That led to the very first FDA approval of an anticancer agent [pembrolizumab] based on a cancer’s specific genetic profile and not the site where the tumor originates. That fundamentally changes how we think about things and potentially how the FDA will move forward in approving drugs.
The amount of individual variation in cancer patients’ tumors suggests that combinations of immunotherapy agents are the path forward.
Dr. Chan: I totally agree. And that’s a good segue into some of the things that we’re going to do in the Center for Immunotherapy and Precision Immuno-Oncology. We want to use big data to rationally design next-generation combination therapies. Some of the things that we’re doing already, based on this concept, have pushed response rates for hard-to-treat cancers like renal cell carcinoma to about 70% to 80% with the right immunotherapy combinations. I’ve been treating patients for a long time, and to see response rates that were stuck at 1%-2% go beyond 70% is unbelievable.
Are those response rates durable?
Dr. Chan: Yes. And I think this is just the tip of the iceberg. Using big data and identifying the new sets of rules that regulate and define success in this new family of therapies that involve the immune system are critical. With the advent of high-throughput immunoprofiling capabilities, we can really understand what drug combinations to use. This will ultimately be helpful for patients in clinical trials because the chances of something working are going to be much greater and patients will benefit even in early-phase trials. It will also save a lot of resources and allow us to accurately and efficiently design large phase III confirmatory trials.
If you’re doing true precision immuno-oncology, with individually tailored treatments, how do you test that?
Dr. Chan: Cancers have multiple levels of differences and similarities. At the fundamental level, Patient A’s cancer may have different mutations than Patient B’s cancer. But when you move a bit broader, there are commonalities like high mutation burden or hypermethylation that can be targeted and used to design molecular-based trials, such as basket trials. A further step is an N of 1 trial design, where one can profile an individual patient and use algorithms to determine what the targeted lesions are likely to be susceptible to.
Enterprise-level cancer profiling enables the application of this philosophy — that every patient’s tumor may be different, but there may be certain combinations of mutations that enable effective targeting. Identifying these immunotherapy targets is one of the most active fields in cancer research. It takes a team: people running clinical trials, computational engineers, bioinformaticians, experimental immunologists. There are a lot of very talented people here at the Taussig Cancer Institute and the Lerner Research Institute, the Robert J. Tomisch Pathology & Laboratory Medicine Institute, and all across Cleveland Clinic. The reason I was excited to come here is because the foundation for a highly impactful translational enterprise for immunotherapy is already here.
Did the international scale of Cleveland Clinic’s health system factor into your decision to relocate?
Dr. Chan: I think the footprint Cleveland Clinic has established, being a global enterprise, allows immunotherapy development to operate at a much higher level. We’re realizing, for instance, that people around the globe have different responses to treatment, and the utility of immunotherapy may vary in different places. There’s global variation, not only in cancer but in infectious diseases. We have the opportunity to conduct clinical trials, develop therapies and improve the understanding of immuno-oncology. We want patients throughout the Cleveland Clinic system to have access to these clinical trials, to be able to get their mutations profiles, and for tailored therapies to be available based on these data. The goal is to enhance immunotherapy capability at all of our different sites, so patients in each part of the world can benefit. We have opportunities to make an impact not just in cancer treatment, but in other areas such as long-term rejection in organ transplant. Cleveland Clinic is one of the largest organ transplant centers in the world. It’s a great place to tackle these questions.
Will the center recruit additional researchers as well as work with existing ones?
Dr. Chan: Yes. For example, we have a mandate to recruit folks who can help develop the next generation of engineered CAR T-cells, going beyond CD 19 — finding new targets, more accurate targets, for solid tumors, for instance. This will be in collaboration with the Case Comprehensive Cancer Center, which has a state-of-the-art GMP-compliant cellular therapy manufacturing facility with six cleanrooms. There are very few like it in the United States in academic institutions. This will be a perfect seed to begin to develop new agents here that will eventually go for IND [investigational new drug] status.
You’ve mentioned checkpoint inhibitors and engineered T-cells. What about cancer vaccines? Will that be a research priority?
Dr. Chan: The major focus of our immunotherapy efforts is vaccine development. This is something we’re really going to encourage and work on collaboratively … to build a cancer vaccine program at Cleveland Clinic. The vaccine world has undergone monumental shifts. In the past, people were largely targeting proteins that were expressed throughout the body, and in the absence of immune checkpoint blockade, there was a lot of tolerance. That’s why for decades cancer vaccines have really not advanced. Partly as a result of our initial findings that tumor mutations are the targets of immunotherapy, the focus of cancer vaccines is now shifting to target neoantigens – these mutations that develop that are foreign to the body.
As a radiation oncologist, you’re caring for cancer patients as well as conducting research. Why do you do both?
Dr. Chan: I’ll be seeing brain cancer patients and am very much looking forward to working with my colleagues in the Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center. Depending on the type of brain tumor, you can make a big difference. Some are curable, and there’s a lot of joy in that. Taking part in clinical activity is critical for translational research, which is what we’re all about. It pushes you to keep up with clinical literature, with what’s happening in the clinical trial space, because your patients are depending on it. I cannot ever see myself not seeing patients.
Considering the rapid pace of recent progress in immunotherapy and precision immuno-oncology, where do you expect the field will be in 10 or 20 years?
Dr. Chan: My dream is that we no longer need the center – that we can cure cancers, or at least extend patients’ lives, by making cancer a chronic illness. But I think I would be happy if we were able to control several more diseases, if we were able to identify new therapeutic combinations and modalities that help push understanding forward. If our efforts allow patients to respond better to current and new immunotherapies and experience deep disease remission, so that a parent can see their child graduate from college or another can meet their new grandchild when previously that would have been impossible, I would call that a success.
MD Anderson immunologist Jim Allison awarded Nobel Prize
Jim Allison, Ph.D., chair of Immunology and executive director of the immunotherapy platform at The University of Texas MD Anderson Cancer Center, today was awarded the 2018 Nobel Prize in Physiology or Medicine for launching an effective new way to attack cancer by treating the immune system rather than the tumor. Allison is the first MD Anderson scientist to receive the world’s most preeminent award for outstanding discoveries in the fields of life sciences and medicine.
“By stimulating the ability of our immune system to attack tumor cells, this year’s Nobel Prize laureates have established an entirely new principle for cancer therapy,” the Nobel Assembly of Karolinska Institute in Stockholm noted in announcing the award to Allison and Tasuku Honjo, M.D., Ph.D., of Kyoto University in Japan.
“I’m honored and humbled to receive this prestigious recognition,” Allison said. “A driving motivation for scientists is simply to push the frontiers of knowledge. I didn’t set out to study cancer, but to understand the biology of T cells - these incredible cells travel our bodies and work to protect us.”
Allison started his career at MD Anderson in 1977, arriving as one of the first employees of a new basic science research center located in Smithville, Texas. He was recruited back to MD Anderson in November 2012 to lead the Immunology Department and to establish an immunotherapy research platform for MD Anderson’s Moon Shots Program.
“Jim Allison’s accomplishments on behalf of patients cannot be overstated,” said MD Anderson President Peter WT Pisters, M.D. “His research has led to life-saving treatments for people who otherwise would have little hope. The significance of immunotherapy as a form of cancer treatment will be felt for generations to come.”
The prize recognizes Allison’s basic science discoveries on the biology of T cells, the adaptive immune system’s soldiers, and his invention of immune checkpoint blockade to treat cancer.
Allison’s crucial insight was to block a protein on T cells that acts as a brake on their activation, freeing the T cells to attack cancer. He developed an antibody to block the checkpoint protein CTLA-4 and demonstrated the success of the approach in experimental models. His work led to development of the first immune checkpoint inhibitor drug. Ipilimumab was approved for late-stage melanoma by the U.S. Food and Drug Administration in 2011.
His drug, known commercially as Yervoy, became the first to extend the survival of patients with late-stage melanoma. Follow-up studies show 20 percent of those treated live for at least three years with many living for 10 years and beyond, unprecedented results. Subsequent research has extended this approach to new immune regulatory targets, most prominently PD-1 and PD-L1, with drugs approved to treat certain types and stages of melanoma, lung, kidney, bladder, gastric, liver, cervical, colorectal, and head and neck cancers and Hodgkin’s lymphoma. Clinical trials are underway in many other cancer types.
“I never dreamed my research would take the direction it has,” Allison said. “It’s a great, emotional privilege to meet cancer patients who’ve been successfully treated with immune checkpoint blockade. They are living proof of the power of basic science, of following our urge to learn and to understand how things work.”
“Science advances on the efforts of many,” Allison said. “A succession of graduate students, postdoctoral fellows and colleagues at MD Anderson, the University of California, Berkeley, and Memorial Sloan Kettering Cancer Center played important roles in this research.”
Allison’s ongoing leadership at MD Anderson focuses on improving knowledge of how these drugs work to extend the benefits of immunotherapy to more patients with more types of cancer. He continues his own research, focusing on the details of immune response to cancer and identifying new targets for potential treatment.
He also leads the immunotherapy platform for MD Anderson’s Moon Shots Program™, which conducts immune monitoring by analyzing tumor samples before, during and after treatment, aiming to understand why these drugs work for some patients but not for others. The platform works with more than 100 immunotherapy clinical trials at MD Anderson addressing a variety of cancers. The platform also collaborates with pharmaceutical companies to help them develop new drugs and combinations to better treat cancer.
“We need these drugs to work for more people,” Allison said. “One challenge is that the clinical success has outrun our scientific knowledge of how these drugs work and how they might best be combined with other therapies to improve treatment and reduce unwanted side effects. We need more basic science research to do that.”
Allison has collaboratively worked with scientists around the globe to expand the field of immunotherapy. Some of his leadership positions include serving as a co-leader of the Stand Up To Cancer-Cancer Research Institute Cancer Immunology Dream Team and as a director of the Parker Institute for Cancer Immunotherapy (PICI). Allison also is deputy director of the David H Koch Center for Applied Research of Genitourinary Cancers at MD Anderson and holds the Vivian L. Smith Distinguished Chair in Immunology.
Crucial funding for his research over the years has come from the National Institutes of Health, particularly the National Cancer Institute, the Cancer Prevention & Research Institute of Texas, Howard Hughes Medical Institute, the Cancer Research Institute, Prostate Cancer Foundation, Stand Up to Cancer and PICI.
Allison will be honored at Nobel ceremonies in Stockholm in December. The Nobel Prize in Physiology or Medicine has been awarded 108 times to 214 Nobel Laureates between 1901 and 2017.
Novel form of immunotherapy could revolutionize cancer treatment
Fig. 1: Local RT eliminates late-stage MC38 tumors in Sirpα−/− mice but not WT mice. From: Intratumoral SIRPα-deficient macrophages activate tumor antigen-specific cytotoxic T cells under radiotherapy
A novel form of macrophage-based immunotherapy is effective at treating a broad spectrum of cancers, including those at advanced stages, according to a groundbreaking study led by Georgia State immunology professor Yuan Liu.
Liu's treatment works by leveraging macrophages, specialized white blood cells involved in the detection and elimination of cancer cells and other pathogens. Macrophages also activate T-cells which then attack and destroy cancer cells. Under normal conditions, this system works well to limit the growth of abnormal cells. However, cancer cells are tricky. Macrophages are vulnerable to cancer cells masquerading as healthy cells by co-opting mechanisms normal cells rely on that evade immune surveillance and detection. These mechanisms can profoundly increase cancer's ability to grow and resist traditional treatment.
This new immunotherapy alters macrophages by knocking out Signal-regulatory protein α (SIRPα), a receptor whose primary function is to prevent macrophages from engulfing and destroying healthy cells. Cancer cells often exploit SIRPα by expressing a marker (CD47) that disguises them as normal cells. In the animal study, published in Nature Communications, Liu and her team found that Sirpα-deficient macrophages initiate a robust immune response against cancer by triggering inflammation and activating tumor-specific T-cells.
The immune system is built to fight off invaders and aberrant cell growths like cancer. But cancer can also suppress and subvert the natural immune response by making it difficult for the body to recognize cancer cells as abnormal. While immunotherapy, which helps recruit the immune system to attack cancer cells, has revolutionized the treatment of tumors, the therapies only work for a limited number of patients.
"Scientists recognize that tumor-specific T-cells are the best weapon we have against cancer, but immunosuppression prevents them from doing their job," Liu said. "Our treatment uses macrophages like a general to call up an army of T-cell soldiers to kill cancer."
The study demonstrates the treatment is effective—and does not destroy large amounts of healthy cells—when delivered locally to the tumor site in conjunction with radiation therapy (RT), one of the cornerstone treatments for cancer.
"To kill the cancer without harming the patient, you need to localize the effects," Liu said. "We developed a method that is very effective while minimizing the global adverse effects."
The researchers found that local RT cured colorectal cancer and two types of pancreatic cancer in SIRPα-deficient mice with advanced tumors. The findings are significant, given that colorectal and pancreatic cancers are often treatment-resistant with high mortality rates.
The mice in the study developed inflammatory immune responses, and in most cases the tumors stopped growing immediately after irradiation. Within four to 12 days, mice with small and medium tumors had cleared the cancer completely, without apparent long-term adverse effects, and the animals remained tumor-free for the remainder of the study. In general, mice that were cured of their cancer exhibited similar longevity (about 18 months) as healthy mice.
The treatment also prevented one of the major negative effects of RT—its tendency to drive a strong wound-healing response that can result in the regrowth of cancer, as the local immune response is suppressed to promote new tissue growth and repair at the site of the RT. This mechanism, however, was absent post-RT in the SIRPα-deficient mice.
The mice exhibited long-lasting immunity to the cancer, which Koby Kidder, a Ph.D. student at Georgia State and co-author of the study, said is the result of an immune response robust enough to control the tumor cells throughout the body. Even when the cured mice were injected with new cancer cells, these cells failed to form tumors, suggesting the animals had acquired long-term immunity that prevented tumor recurrence.
"The reason we achieved such a high degree of efficacy is that we directly used the macrophage to mobilize other cells within the body," Kidder said. "The mounting of a consummate anti-tumor immune response in concert with removing immunosuppressive factors (cells and cytokines) from the tumor microenvironment drastically affected the immune response. By removing SIRPα and combining it with radiotherapy, we elicited such a robust response it essentially cured the cancer."
The study demonstrates SIRPα is a master controller of immunity inside the tumor microenvironment, directing post-RT wound healing, strengthening immunosuppression, conferring treatment resistance and allowing the cancer to progress. In the absence of SIRPα, however, antitumor immune responses are significantly enhanced.
The treatment has the potential to become a "pan-cancer therapy," meaning it could be used to cure a broad spectrum of cancers, including those at advanced stages with metastasis. The study provides strong proof-of-concept for developing Sirpα-negative macrophage-based cell therapies, Liu said.
The cell therapy approach has already been tested against the entire NCI-60 cancer panel—made up of 60 various human tumor cell lines representing leukemia, melanoma, lung, colon, brain, ovary, breast, prostate and kidney cancers—and has been found to be effective. The researchers are applying for approval of the therapy as an investigational new drug by the U.S. Food & Drug Administration and hope to begin human clinical trials in 2022.
Liu has received grants from the National Cancer Institute, the Georgia Research Alliance and Biolocity to support this research.
"Currently, the treatments using immune therapy only benefit a small percentage of patients," Liu said. "This therapy has already proven effective in the laboratory and could be the key to fighting all types of cancer. This is basically a battlefield in the body, and if we are able to activate the proper delivery signals, our bodies win."