immunotherapy

Fifteen students and four women were taken from a school in the state of Sokoto. The army is still searching for hundreds abducted in Kaduna state on Thursday. Also: Indonesia investigates how two pilots fell asleep at the controls for almost half an hour, and scientists report a breakthrough in the quest to resurrect the woolly mammoth.

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Keith Flaherty is the director of clinical research at the Massachusetts General Hospital Cancer Center and a previous guest on The Drive. In this episode, Keith first delves into the statistics on cancer's prevalence as we age, underscoring the significance of finding effective treatments and early detection methodologies. He touches on the history of cancer therapeutics and illuminates the notable enhancements in cancer therapy within the last decade that are setting the stage for a promising future. He goes into detail on the potential of immunotherapy and therapies that can combat cancer’s evasive tactics while explaining some of the existing challenges around specificity, cost, and scalability. Additionally, Keith highlights the significant leap in early detection methodologies, namely liquid biopsies, which have the potential not only to determine if a cancer is present in an early stage, but also identify the possible tissue of origin.

We discuss:

• Keith’s interest and expertise in cancer [3:15];
• Cancer deaths by decade of life, and how cancer compares to other top causes of death [7:00];
• The relationship between hormones and cancer [12:00];
• The link between obesity and cancer [18:45];
• Current state of treatments for metastatic cancer and reasons for the lack of progress over the decades [22:30];
• The interplay between the immune system and cancer cells [32:00];
• Different ways cancer can suppress the immune response, and how immunotherapy can combat cancer’s evasive tactics [39:30];
• Elimination of a substantial portion of cancers through immune cell engineering faces challenges of specificity, cost, and scalability [52:15];
• Why TIL therapy isn’t always effective, and the necessity for multimodal therapy to address various aspects of the cancer microenvironment [1:01:00];
• Potential developments in cancer therapy over the next five years: T-cell activation, metabolic interventions, targeting tumor microenvironments, and more [1:06:30];
• The challenge of treating metastatic cancer underscores the importance of early detection to improve survivability [1:19:15];
• Liquid biopsies for early detection of cancer and determining the possible tissue of origin [1:24:45];
• Commercially available cancer screening tests [1:33:45];
• How to address the disparity in cancer care, and the exciting pace of progress for cancer detection and treatment [1:40:15]; and
• More.

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Josh Rabinowitz is a Professor of Chemistry and Integrative Genomics at Princeton University, where his research focuses on developing a quantitative, comprehensive understanding of cellular metabolism through the study of metabolites and their fluxes. In this episode, Josh focuses the discussion on three main topics: metabolomics, NAD (and its precursors), and cancer metabolism. The metabolomics discussion starts with a broad definition of metabolism, metabolites, and fluxomics before diving deep into glucose metabolism, lactate as a fuel, movement of lactate, and the regulation of these substrates. He then gives a detailed explanation of the electron transport chain and Krebs cycle and their implications with respect to both drugs and nutrition while also explaining how NAD is central to the process of energy generation. He then discusses the age-related decline in NAD and what current literature says about efforts to increase NAD through intravenous or oral supplementation with the precursors NMN and NR, including whether doing so provides any advantage to lifespan or healthspan. Finally, Josh ends the conversation talking about cancer metabolism and how one particular intersection between cancer metabolism and immunotherapy might provide a hopeful outlook on the future of cancer treatment.

We discuss:

• Josh’s background and unique path to becoming a research scientist at Princeton [3:30];
• What sparked Josh’s early interest in metabolism [11:15];
• Metabolomics 101: defining metabolites and how they are regulated [16:30];
• Fluxomics: metabolism as a system in action [26:00];
• The Randle Hypothesis: glucose and fatty acids compete as substrates for oxidation [33:30];
• The important role of lactate as an alternate fuel [36:30];
• Fasting lactate levels as a potential early indicator of metabolic dysfunction [48:00];
• The beauty of the Krebs cycle and the role of NAD in energy production [53:15];
• How the drug metformin acts on complex I of the electron transport chain [1:05:00];
• The difference between NADH and NADPH [1:08:45];
• NAD levels with age, and the efficacy of supplementing with intravenous NAD [1:10:45];
• The usefulness of restoring NAD levels and efficacy of oral supplementation with NAD precursors NR and NMN [1:22:15];
• Exploring the hypothesis that boosting NAD levels is beneficial [1:32:30];
• Cancer metabolism and the intersection with immunotherapy [1:39:00];
• Making cancer a chronic disease: exploiting the metabolic quirks of cancer, augmenting the immune system, and more [1:46:15];
• The challenge of treating pancreatic cancer [1:50:30];
• Epithelial cancers that might respond to metabolic approaches to therapy [1:56:30];
• Josh’s hopeful outlook on the future of cancer treatment [1:59:00];
• Nutritional approaches to cancer attenuation [2:00:15];
• What makes Princeton University special [2:06:15];
• More.

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CAUTION: This episode contains references to skipping meals and may be triggering for those with eating disorders.

Today’s guest believes that the decisions we make every day about what we eat have a huge influence on our health. Dr William Li is a medical doctor and the author of the international bestseller, Eat to Beat Disease: The Body's Five Defense Systems and the Foods That Could Save Your Life. He works in a field of research called Food as Medicine and having been involved with the development of many different drugs over the past few decades, he is passionate about using scientific rigour to analyse the specific benefits of food.

We discuss the five health defence systems that exist within our bodies: angiogenesis (growing of new blood vessels), stem cell regeneration, the gut microbiome, DNA protection and the immune system. These systems maintain our health and help us heal when disease damages our body. Dr Li explains how specific foods can strengthen these natural defence systems.

We talk about cancer, how tumours grow, and where food can play a role in terms of prevention as well as part of the treatment. Dr Li shares the research about the amazing benefits of green tea for cancer prevention. We also talk about the impact that fasting has on various health systems within our body.

Dr. Li’s ground-breaking work is really changing the way we look at how food impacts our health and I think that by the end of this conversation, you will look at food through a different lens. And I'm pretty sure that it's going to inspire you to make a few changes next time you go to the supermarket - it certainly did for me. I hope you enjoy listening. 

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Steve Rosenberg is the Chief of Surgery at the National Cancer Institute, a position he has held continuously for the past 47 years. Steve is a pioneer in the field of immunotherapies for cancer and a recipient of nearly every major award in science. In this episode, Steve discusses his inspiration for devoting his career to cancer research and describes his keen observation of two cases of spontaneous cancer remission, driving him to learn how to harness the immune system to treat cancer. Steve’s personal story essentially serves as a roadmap for the field of immunotherapy, from the very non-specific therapies such as interleukin-2, the discovery of tumor-infiltrating lymphocytes, checkpoint inhibitors, CAR T-cells, and adoptive cell therapy. Perhaps most importantly, Steve expresses his optimism for what lies ahead, especially in the face of some of the more recent discoveries with respect to tumor antigenicity. Finally, Steve discusses the human side of cancer which helps him to never lose sight of why he chose to become a physician.

We discuss:

• Steve’s childhood and inspiration to become a physician and medical researcher [3:15];
  
• Patients that influenced Steve’s thinking about cancer and altered the course of his career [13:15];
  
• The discovery of antigen presentation, Steve’s first job, and why he knew he wanted to study cancer [19:30];
  
• Cancer treatment in the early 1970’s and Steve’s intuition to utilize lymphocytes [26:45];
  
• Cancer cells versus non-cancer cells, and why metastatic cancer is so deadly [31:45];
  
• The problem with chemotherapy and promise of immunotherapy [38:30];
  
• How the immune system works and why it seems to allow cancer to proliferate [43:15];
  
• Steve discovers how to use interleukin-2 to mediate cancer regression [52:00];
  
• The immunogenic nature of certain cancers and the role of mutations in cancer [1:03:45];
  
• The improbable story of how CAR T cell therapy was developed [1:16:30];
  
• The discovery of tumor infiltrating lymphocytes (TIL) and engineering of T cells to recognize specific antigens [1:28:00];
  
• Steve’s experience treating President Ronald Reagan’s colon cancer [1:36:00];
  
• Why Steve has turned down many tempting job offers to focus on his research at the National Cancer Institute [1:41:00];
  
• The role of checkpoint inhibitors in cancer therapy and the promise of adoptive cell therapy [1:43:00];
  
• Optimism for using immunotherapy to cure all cancers [1:48:00];
  
• The human side of cancer and the important lessons Peter learned from working with Steve [1:52:15]; and
  
• More

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In this episode, Keith Flaherty, director of clinical research and targeted cancer therapy at Massachusetts General Hospital, shares his vast wealth of knowledge in cancer starting with the history of treatment from chemotherapy to radiation to surgical therapy and where those methodologies seemed to have leveled off. He also walks us through the timeline of advancements (and lack there of) from when the War on Cancer was declared in the 1970s, through the sequencing of the entire human genome, and all the way to today. Keith dives into the topic of immunotherapy, probably the most exciting recent development in cancer therapy, and also provides us a rundown of his notion of a different approach to cancer that attacks all the essential pillars of cancer growth and survival. Finally, we talk a little bit about liquid biopsies, we discuss the roles of CRISPR and other potentially over-hyped therapies with respect to cancer. We also touch on stem cell therapy a bit, as well as some other common cancer-related questions such as the role of vitamin D and sun exposure in melanoma, and much more.

We discuss:

• Growing up around medicine, and finding a career that you love [7:30];
• Medicine as a career, limitations of the med school teaching approach, and the dynamic and accelerating field of medicine and technology [16:30];
• Explaining chemotherapy, radiation, and how a cancer develops [23:45];
• Surgical oncology, cure rate of solid tumors, and survival rate after tumor removal  [33:15];
• 25 years after the War on Cancer is declared, gene sequencing, and why Keith’s was fascinated by the HIV case study [37:15];
• Cancer immunotherapy: History, how it works, and why some cancers respond and others don’t [46:00];
• MHC complexes, and cancer cloaking mechanisms [56:00];
• Comparative biology of cancer: Why some cancer can evade immune detection better than others [1:03:00];
• What we learned from the Cancer Genome Atlas Project [1:07:00];
• Defining targeted therapy, HER2 breast cancer, chronic leukemia, and the translocation of chromosomes [1:12:00];
• Tumor protein P53, the most famous tumor suppressor gene and its ubiquity in cancer [1:17:45];
• Activated oncogenes, the RAS pathway, PI3 kinase, RAF gene, and Keith’s “aha moment” [1:24:15];
• Advice for starting your career as a scientist/clinician [1:37:00];
• Fusion-driven cancers, targeted therapy, and the Bcr-Abl/chronic myelogenous leukemia case study [1:39:45];
• Targeted therapy for fusion-driven solid tumors, adjuvant systemic therapy, and the HER2 breast cancer example [1:53:00];
• Advancing melanoma treatment, survival, and cure rates with BRAF-MEK combo therapy [1:59:15];
• The fundamental pillars of cancer growth and survival, and the toolkit we need to attack cancer from all angles [2:02:40];
• Peter’s clinical framework for thinking about cancer and how Keith might improve it, and how the biotech environment is hampering our ability to put together novel cancer treatments [2:05:00];
• How useful is CRISPR in terms of tumor suppressing? [2:16:15];
• Liquid biopsies as a therapeutic monitoring tool [2:18:00];
• Stem cell therapy: The efficacy and potential risks [2:25:15];
• Aging and cancer: Is cancer inevitable? [2:28:45];
• Vitamin D supplements, sun exposure, melanoma, and exercise [2:32:30];
• How and why Keith has straddled the line between science/research and industry/drug companies, and the importance of getting more voices of practitioners at the table [2:42:00]; and
• More.

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In this week's SYSK Select episode, about 30-40 percent of humans suffer from some sort of allergy. The big joke, though, is that every sufferer is the victim of mistaken identity. Allergies are the result of a hypersensitive immune system mistaking a harmless protein for a foreign invader.

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