Podcast Summary
From Holocaust survivor to cancer research pioneer: Holocaust survivor Dr. Steve Rosenberg dedicated his career to alleviating suffering through immunotherapy discoveries, from interleukin-2 to CAR T cells and adoptive cell therapy.
Dr. Steve Rosenberg, a pioneer in the field of immunotherapy with a career spanning over five decades, was inspired by the suffering he witnessed during the Holocaust to become a doctor and researcher focused on alleviating suffering and preventing future suffering. His work in the field of immunotherapy, from the discovery of interleukin-2 to the development of checkpoint inhibitors, CAR T cells, and adoptive cell therapy, has been instrumental in advancing cancer treatment. His optimism for what lies ahead in immunotherapy research, coupled with his dedication to helping patients, makes him an inspiring figure in the scientific community. For those interested in learning more about his journey and the process of scientific discovery, Rosenberg's book "The Transformed Cell" is highly recommended.
From high school to Harvard: The interviewee's unconventional educational journey: The interviewee's thirst for knowledge and desire to make an impact led him to leave a residency to pursue a PhD at Harvard
The interviewee's drive for continuous learning and pursuit of knowledge led him to an unconventional educational path. He excelled in high school and entered a combined bachelor's MD program at Hopkins, knowing he would later pursue a PhD. Hopkins provided a nurturing environment for his scientific curiosity, and he was inspired by the brilliant minds around him. He chose to get a PhD in biophysics at Harvard to avoid being intimidated by complex scientific concepts and to acquire a broad background in the sciences. After completing his residency, he took a break to earn his PhD and later joined the NIH. Franny Moore, the chief of surgery at Hopkins, was a significant figure who inspired him with his intellectual prowess. Leaving a residency to pursue a PhD was unusual at the time, but the interviewee's thirst for knowledge and desire to make an impact drove him to make that choice.
Encounter with a cancer patient's recovery sparks curiosity: A rare recovery from cancer ignited a lifelong passion for research, inspiring an unconventional experiment and shaping a successful career in science, fueled by a supportive mentor.
The interviewee's encounter with a patient who had spontaneously regressed from gastric cancer without any treatment during his residency in 1968 significantly influenced his career in science. This rare event sparked his curiosity and led him to attempt an experimental treatment using blood transfusion from the recovered patient to another patient with gastric cancer. Although the experiment did not yield any results, it marked the beginning of his exploration into the field of cancer research. The interviewee's respect for his supervisor, Frannie, who supported his career aspirations despite the unconventional path, also played a crucial role in his journey.
Two patients' experiences shaped Dr. Thomas's interest in cancer immunology: Dr. Thomas's curiosity about the immune system's role in cancer was sparked by observing a cancer in remission and a cancer's spread due to immunosuppressive medications, leading him to the NCI for groundbreaking research
The experiences of two patients during the late 1960s and early 1970s influenced Dr. E. Donnall Thomas's interest in the immune system's role in cancer. The first patient's gastric cancer went into remission after the immune system rejected a transplanted tumor, while the second patient's kidney transplant contained a hidden renal cancer that spread due to immunosuppressive medications. These events demonstrated the immune system's potential to reject large, invasive cancers if given a strong enough stimulus. At the time, the understanding of the human immune system's role in cancer was limited, with no identified cancer antigens or manipulations. However, Dr. Thomas's experiences fueled his curiosity and led him to the National Cancer Institute, where he has held the position of chief of surgery for over 46 years. The NCI offered the opportunity to make significant progress in cancer research and create medicine of the future. Despite an offer to stay at Harvard's Dana Farber, Dr. Thomas chose to join the NIH, drawn by its resources, commitment, and innovative spirit.
Leaving Harvard for a Personal Mission at NIH: A researcher, driven by personal experiences, left a prestigious position to pursue groundbreaking cancer research at NIH, making significant contributions to immunology despite resistance.
The interviewee, driven by a personal connection to cancer due to childhood experiences, made a decision to leave a prestigious position at Harvard's Brigham and Women's Hospital to pursue research at the National Institutes of Health (NIH) in the late 1970s. Despite resistance from his superior, he followed his convictions and made significant contributions to the field of immunology in cancer research. The National Cancer Act, which increased funding for cancer research outside of the NIH, had less impact on the intramural research the interviewee was focused on. He arrived at the NIH with a clear research agenda, driven by a desire for a groundbreaking discovery rather than incremental advances in cancer treatment through surgery, radiation therapy, and chemotherapy. He believed the immune system held the key to a major breakthrough and dedicated his research to studying it.
Early experiments with pig lymphocytes mark the beginning of immunotherapy research: Dr. Ehrlichman's pioneering work in the 1970s used pig lymphocytes to treat human cancer, paving the way for immunotherapy's development and revolutionizing cancer treatment.
Dr. Ehrlichman's groundbreaking research in the field of immunotherapy began with a desperate attempt to use immune cells from pigs to treat human cancer in the early 1970s. At the time, keeping lymphocytes alive outside the body was impossible, and his experiments involved implanting human tumors into mini-pigs, removing inflamed lymph nodes, and administering the reactive lymphocytes to patients. Although nothing happened, this marked the beginning of his pursuit to manipulate lymphocytes outside the body, which became possible with the discovery of T-cell growth factor in 1976. This opened the door to growing pigs' lymphocytes with anti-tumor activity, which could be used to treat cancer. It's important to note that cancer is defined by its uncontrolled growth and ability to spread to other parts of the body. The difference between epithelial tumors (solid tumors) and hematologic tumors (blood cancers) was significant in 1974, with epithelial tumors accounting for 90% of cancer deaths. Dr. Ehrlichman's early work laid the foundation for the development of immunotherapy, which has since revolutionized cancer treatment.
Limited progress in curing metastatic cancers: While treatments like chemotherapy and targeted therapies extend survival for some metastatic cancers, they don't offer a cure for most patients, and their high cost underscores the need for more effective treatments
While we have made progress in extending median survival for some metastatic cancers, overall survival rates have not significantly changed. Currently, for most solid epithelial cancers, if they spread beyond the initial site and cannot be surgically removed, the patient's death rate is 100%. There are only a few exceptions, such as coriocarcinoma, germ cell tumors, melanoma, and renal cancer. Despite advancements in treatments like chemotherapy and targeted therapies, these treatments only provide temporary benefits and significant extensions in survival, but they do not offer a cure for most patients. The high cost of these treatments, which can prolong life by a few weeks or months, highlights the urgent need for more effective and curative treatments for metastatic cancers.
Understanding the difference between cancer cells and normal cells for effective cancer treatment: Immunotherapy is a promising cancer treatment approach due to the immune system's ability to specifically recognize and eliminate cancer cells, unlike chemotherapy and radiation therapy which can harm normal cells.
The challenge in cancer treatment lies in selectively targeting and destroying cancer cells without harming normal cells. Chemotherapy and radiation therapy have limitations in achieving this selectivity. Immunotherapy, on the other hand, offers immense potential due to the immune system's exquisite sensitivity and specificity in recognizing and destroying foreign antigens, such as cancer cells. The immune system, which includes T-cells and B-cells, is constantly patrolling the body, recognizing and eliminating foreign antigens, like viruses, by producing antibodies or directly attacking infected cells. This process, called an immune reaction, results in long-lasting immunity. Cancer cells, however, have unique properties that make them different from self: they fail to respond to cell cycle signaling, leading to unregulated growth, and they can leave the site of origin and grow elsewhere. Understanding this difference and the immune system's ability to recognize and eliminate foreign antigens provides a promising approach to developing new cancer treatments.
The immune system recognizes cancer cells but can't always eliminate them: The immune system identifies cancer cells but often fails to eliminate them due to weak immune response or cancer's ability to suppress it. Interleukin II and checkpoint modulators are potential treatments to enhance immune response.
Cancer exists because the immune system, despite recognizing mutations in cancer cells, is not always strong enough to eliminate them. These mutations can produce proteins or other molecules that are recognized by the immune system, but the immune reaction is often not vigorous enough to prevent the tumor's growth. Cancer cells also develop ways to suppress the local immune reaction, such as producing inhibitory molecules like TGF beta and interleukin 10. The balance between the aggressive immune reaction and the inhibitory factors is the "holy grail" of finding effective cancer treatments. Interleukin II was a major breakthrough in cancer research after Gallo's discovery, as it allowed for the growth of lymphocytes in vitro and the stimulation of the immune system in vivo. However, early studies with lymphocine activated killer cells, which were stimulated by interleukin II, were a false alarm as they only had an impact on tiny, non-vascularized tumors in mice. Instead, interleukin II and other treatments, like checkpoint modulators, hold promise in stimulating the immune system to effectively recognize and eliminate cancer cells.
The first patient with metastatic melanoma showed tumor regression after receiving interleukin 2 in 1984.: Interleukin 2's discovery led to the understanding that the immune system could cause cancer to disappear, paving the way for further research in cell transfer, gene modification, and other areas.
The discovery of using interleukin 2 to cause cancer regression was a groundbreaking moment in cancer research. Despite numerous experiments and clinical trials in the 1970s and early 1980s, it wasn't until 1984 that the first patient with metastatic melanoma showed tumor regression after receiving interleukin 2. This breakthrough came after altering the administration schedule and dealing with the toxicity. The impact of this discovery was significant as it showed that the immune system could cause a cancer to disappear, leading to further research in cell transfer, gene modification, and other areas. The researcher, who was working on this project, shared that coping with the many patient deaths before this breakthrough was challenging, but his intuition and previous observations kept him motivated. Success, as Abraham Lincoln once said, is moving from failure to failure without losing enthusiasm.
The Long and Challenging Journey of Discovering Effective Immunotherapies for Cancer: The high mutation rates in melanoma and renal cell cancer increase the likelihood of developing foreign proteins, making them responsive to immunotherapies. Immunotherapies have led to significant advancements in cancer treatment, with a higher likelihood of response in cancers with a high number of mutations.
The discovery of effective immunotherapies for diseases like melanoma and renal cell cancer was a long and challenging process. Dr. Steven A. Rosenberg, the researcher behind this breakthrough, recalls feeling the weight of the world on his shoulders as he tried to find a solution while balancing his family life. He credits his wife Alice for her unwavering support during this time. The reason these specific cancers responded to immunotherapy was not fully understood at the time, but now we know it's due to their high mutation rates, which increase the likelihood of developing foreign proteins that can be recognized by the immune system. This discovery has led to significant advancements in cancer treatment. Despite treating over 600 patients with interleukin-2, they only saw responses in those with melanoma and renal cell cancer. The median number of mutations in common cancers like breast, colon, and pancreatic cancer ranges from 60 to 150, with a likely median of around 110. Pediatric cancers typically have fewer mutations. The more mutations a cancer has, the higher the likelihood of developing a protein that can be recognized by the immune system, leading to a response to immunotherapy.
The role of seemingly random mutations in causing cancer: Only 1-2% of mutations are immunogenic and can be targeted for therapy. Personalized cancer treatments are crucial as each patient produces unique neoantigens.
While driver mutations in cancers like P53 and K-RAS play a significant role, the accumulation of seemingly random mutations, each with its own property, can also cause cancer when they act in concert with other genes. Surprisingly, only between 1.5% and 2% of all mutations are immunogenic, meaning they can be recognized by the immune system and potentially targeted for therapy. This is due to the fact that for a mutation to be recognized, it must be broken down into small peptides and fit onto the patient's own HLA molecules, which are highly polymorphic and unique to each individual. Furthermore, in a series of nearly 200 patients, each produced at least one unique neoantigen, with only two exceptions having a shared antigen due to a K-RAS mutation. This finding highlights the importance of personalized cancer treatments that target these unique antigens. Despite the ubiquity of driver mutations like P53 and K-RAS, cancer's ability to evade detection by the immune system is still not fully understood and requires further investigation.
Understanding cancer antigens and developing personalized treatments: Despite progress in cancer treatment, the individualized nature and complexity of targeting specific mutations pose challenges for scalability and affordability. CAR T cells offer promise but targeting unique molecules on cancer cells is limited.
While we have made significant strides in understanding cancer antigens and developing personalized treatments, such as CAR T cells, the complexities involved in targeting individual mutations and avoiding healthy cells pose a significant challenge for scalability. In the late 1980s, researchers identified the existence of cancer antigens but struggled to identify shared antigens across different cancer types. Now, with our improved understanding of mutations and cancer antigens, we have the potential to develop broadly applicable treatments for various cancer histologies. However, the highly individualized nature of these treatments, which require targeting specific mutations present only in individual patients, makes development and implementation complex and costly. The discovery of CAR T cells, which can recognize and attack cancer cells using antibody recognition domains, has been a game-changer in cancer treatment. However, the limited number of unique molecules on the surface of cancer cells that are not present on normal cells and can be targeted by CAR T cells further complicates the development process. The potential for developing effective, broadly applicable cancer treatments is exciting, but the challenges of scalability and individualization must be addressed.
First FDA-approved cell and gene therapy from CAR T-cells: Genetically modified T-cells targeting CD19 antigen led to the first FDA-approved cell and gene therapy, revolutionizing cancer treatment. Despite challenges in treating solid tumors, ongoing research holds promise.
The development of CAR T-cell therapy, which uses genetically modified T-cells to target and eliminate cancer cells expressing a specific antigen (CD19), led to the first-ever FDA-approved cell and gene therapy. This breakthrough came from research at the University of Pennsylvania and was initially used to treat lymphoma patients, resulting in complete remissions for many. In 2012, a former fellow from the lab, Ari Bell, founded Kite Pharma to commercialize this treatment, leading to the formation of a Cooperative Research and Development Agreement. Kite Pharma's success in treating lymphoma patients was validated by a multi-institutional study and the sale of the company to Gilead for $11.9 billion in 2017. Despite its success in hematologic cancers, CAR T-cell therapy currently has limited applicability to solid tumors due to the lack of unique antigens on cancer cells that aren't also present on normal cells. However, ongoing research may uncover new ways to make CAR T-cell therapy effective against solid tumors in the future.
Discovery of TIL and development of cancer immunotherapy: In the 1980s, TIL (tumor infiltrating lymphocytes) were discovered, leading to the development of cancer immunotherapies. Despite initial limitations, the discovery marked a significant step forward in cancer treatment, and genetically modified lymphocytes were later used in clinical trials.
While identifying unique antigens for non-essential organs like breast, pancreas, and colon could lead to more effective cell-based therapies against cancer, no such molecules have been identified yet. However, a significant discovery was made in the 1980s when it was found that certain types of lymphocytes, called TIL (tumor infiltrating lymphocytes), could recognize and attack tumors. This led to the development of immunotherapies using these lymphocytes, which showed promising results in melanoma patients. Despite the initial limitations, the discovery of TIL marked a significant step forward in cancer immunotherapy. Later, scientists attempted to genetically modify these lymphocytes to make them even more potent. However, introducing genes into human cells was a new and uncertain territory, requiring careful consideration and regulatory approval. Ultimately, the first clinical trial using genetically modified lymphocytes was approved in the late 1980s, marking a major milestone in the field of cancer immunotherapy.
Early discovery of genetically modified T cells for cancer treatment: The 1980s discovery of genetically modified T cells for cancer treatment stemmed from ethical controversies and led to the development of CAR T cells, with advancements continuing today through efficient targeting of mutations and advanced genetic modification technology.
The discovery of genetically modified T cells for cancer treatment emerged from a groundbreaking experiment in the 1980s involving the use of genetically modified lymphocytes to track cells inside the body. This research, which faced ethical controversies, led to the development of CAR T cells and the understanding of the role of unique mutations in cancer. In 1985, a pivotal moment came when a team including an oncology expert was called to treat President Reagan for colon cancer due to the availability of advanced medical facilities and technology for high-level government officials. This experience further fueled the research in the field, ultimately leading to the current advancements in immunotherapies. Today, scientists continue to explore ways to more efficiently target mutations and develop more effective immunotherapies using the latest biologic information and genetic modification technology.
Dr. Fearon's commitment to his mission and research kept him at the NCI: Dr. Fearon's dedication to his mission and ongoing research led him to decline high-profile job offers and stay at the NCI. Checkpoint inhibitors, like anti-CTLA-4 and anti-PD-1, revolutionized cancer treatment but require a tumor antigen and come with risks.
During his tenure at the National Cancer Institute (NCI), Dr. Fearon was offered several high-profile job opportunities, including at Georgetown, Johns Hopkins, and the Brigham, but he chose to stay at the NCI due to his mission-focused approach and a desire to continue his research. Another key takeaway is the discussion about checkpoint inhibitors, such as anti-CTLA-4 and anti-PD-1, which work by removing inhibitors on the surface of lymphocytes that prevent an immune reaction. However, these treatments only work if there is a tumor antigen present. While checkpoint inhibitors have been a game-changer in cancer treatment, they also come with risks and can have negative side effects. Dr. Fearon's experience and research have contributed significantly to the understanding and development of these treatments.
Discovering new ways to release the brakes on T cells for cancer treatment: Checkpoint modulators show promise in attacking high mutation rate cancers, but not all patients respond. Adoptive cell therapy using genetically modified lymphocytes holds potential for treating solid organ metastatic cancer patients who don't respond to checkpoint inhibitors alone.
Checkpoint modulators, which release the brakes on T cells, have shown promising results in attacking certain cancers, particularly those with high mutation rates like melanoma and kidney cancer. This discovery, which involves injecting an antibody to release the checkpoint, is a major step forward in immunotherapy. However, not all cancer patients respond to this treatment, as common epithelial cancers have little reactivity against checkpoint modulators. Nevertheless, the potential for adoptive cell therapy, such as genetically modifying lymphocytes to recognize unique antigens, holds great promise for treating the 550,000 patients with solid organ metastatic cancer who do not respond to checkpoint inhibitors alone. With the knowledge that antigens recognized by T cells are present in 80% of common cancers and the engineering problem of isolating and administering these reactivities, a cure for these patients may be on the horizon. The researcher's intuition is that this is the path forward, as the antigens and T cells are known to exist, and the technology is advancing rapidly.
New possibilities for cancer treatment through T cell recognition of mutations: Recent discovery of mutations as T cell antigens opens new avenues for cancer treatment. Sharing knowledge and information, and remaining dedicated to patients are crucial for progress.
The recent discovery of mutations as the antigens that T cells can recognize in cancer is a game-changer in the field of oncology. This realization, which is still very recent, opens up new possibilities for cancer treatment. However, it's important to remember that science progresses through incremental advances, and the next step is to figure out how to effectively harness this new knowledge. Another important lesson from the discussion is the importance of sharing knowledge and information in science, rather than keeping it secret. This openness can lead to faster advancements and ultimately, better outcomes for patients. The speaker emphasized the need to overcome secrecy, whether it's due to personal jealousy or intellectual property protection, to accelerate progress in cancer research. Finally, the speaker emphasized the importance of never retreating from the bedside and remaining dedicated to helping cancer patients, even in the face of difficult odds.
The importance of dedication and motivation in healthcare: Healthcare providers must stay committed to making a difference, even when faced with difficult situations and limited resources, as the belief in doing everything possible to help patients fuels their motivation.
Dedication and motivation are key in caring for patients, even when faced with difficult situations and limited resources. The speaker, who has worked with cancer patients for decades, shared her admiration for those in oncology and her own commitment to improving patient outcomes. She acknowledged the challenges of watching patients suffer and sometimes die despite her best efforts, but emphasized that the motivation to keep trying comes from the belief that she is doing everything possible to help. The speaker also touched on the complexities of the immune system and how it relates to her work, highlighting the importance of both stimulatory and inhibitory components. Overall, her reflections underscore the profound impact of being a healthcare provider and the importance of staying committed to making a difference, even in the face of adversity.
Membership program for deeper insights: Dr. Attia's podcast offers a membership program with exclusive benefits, including comprehensive show notes, private podcast feed, and discounts on recommended products.
Dr. Peter Attia's podcast, The Drive, offers a membership program with exclusive benefits for those interested in diving deeper into the topics discussed. The membership provides comprehensive show notes, access to a private podcast feed, discounts on recommended products, and more. It's important to note that the content on the podcast is for general informational purposes only and should not be considered a substitute for professional medical advice. Dr. Attia takes conflicts of interest seriously and discloses his investments and advisory roles on his website. The speaker expressed gratitude to Dr. Attia for his time and expertise, acknowledging the sacrifice of his time spent on the podcast.
