#177 - Steven Rosenberg, M.D., Ph.D.: The development of cancer immunotherapy and its promise for treating advanced cancers
Dr. Steve Rosenberg, Chief of Surgery at the National Cancer Institute, recounts his 47-year journey in cancer immunotherapy. He shares his inspiration, the development of IL-2, TILs, and CAR T-cells, and his optimism for future individualized treatments targeting unique tumor mutations.
Deep Dive Analysis
15 Topic Outline
Childhood Inspiration and Early Career Path
Influential Patient Cases and the Idea of Immunotherapy
Joining the National Cancer Institute as Chief of Surgery
Defining Cancer and the Deadliness of Metastatic Disease
Limitations of Traditional Cancer Therapies and Promise of Immunotherapy
How the Immune System Works Against Viruses and Cancer
Discovery and Application of Interleukin-2 for Cancer Regression
Understanding Immunogenicity: Melanoma, Mutations, and Neoantigens
The Development and Impact of CAR T-Cell Therapy
Discovery and Engineering of Tumor Infiltrating Lymphocytes (TIL)
Experience Treating President Ronald Reagan's Colon Cancer
Commitment to NCI Research Over Administrative Roles
Mechanism and Impact of Checkpoint Inhibitors
Optimism for Future Immunotherapies Targeting Unique Mutations
The Human Side of Cancer and Importance of Knowledge Sharing
6 Key Concepts
Metastatic Cancer
This refers to cancer that has spread from its original site to other parts of the body. Once cancer becomes metastatic and cannot be surgically removed, the death rate is virtually 100% with current treatments, with only a few rare exceptions.
Antigen
An antigen is a molecule, generally a protein or carbohydrate, that is not normally expressed by the body's tissues and can be recognized as foreign by the immune system's T or B lymphocytes. This recognition triggers an immune response.
Immunogenicity of Cancer
This refers to the ability of cancer cells to provoke an immune response. Cancers with a higher number of mutations, like melanoma or lung cancer, tend to be more immunogenic because these mutations can produce foreign proteins (neoantigens) that the immune system can recognize.
Neoantigens
These are unique antigens produced by mutations in cancer cells that are not present in normal cells. The immune system can recognize these neoantigens, and recent research indicates that about 80% of common epithelial cancers contain T-cells that can recognize these unique mutations.
Chimeric Antigen Receptor (CAR) T-Cells
CAR T-cells are T-lymphocytes genetically engineered to express a chimeric antigen receptor, which is a hybrid molecule combining an antibody's antigen-recognition domain with a T-cell's signaling domain. This allows the T-cell to recognize specific molecules on the surface of cancer cells in a manner similar to an antibody, expanding the range of targets.
Checkpoint Inhibitors
These are antibodies that target specific molecules (like CTLA-4 or PD-1) on the surface of lymphocytes, effectively 'releasing the brakes' on the immune system. By blocking these inhibitory pathways, checkpoint inhibitors allow T-cells to become more active and attack cancer cells, particularly in cancers with a high mutational burden.
7 Questions Answered
Dr. Rosenberg was inspired at age five or six by the horrors of the Holocaust, developing a spiritual desire to alleviate suffering through medical research rather than causing it, and this commitment persisted throughout his education.
One patient experienced a spontaneous regression of widespread gastric cancer, suggesting the body's immune system could reject cancer. Another patient's transplanted kidney inadvertently contained renal cancer, which regressed when immunosuppressive medications were stopped, demonstrating the immune system's potential to cause tumor collapse if strongly stimulated.
Cancer cells exhibit two main properties: uncontrolled growth, meaning they don't stop dividing like normal cells, and the ability to spread from their original site to grow and divide in other parts of the body (metastasis).
For the vast majority of patients with metastatic solid cancers that cannot be surgically removed, the death rate is 100%, meaning current systemic treatments can prolong survival by months or a few years, but rarely achieve a cure, with only a few historical exceptions like choriocarcinoma and germ cell tumors, and more recently melanoma and renal cancer.
While cancer cells have mutations that can produce foreign proteins (neoantigens), the immune response against them is often too small or not vigorous enough to overcome tumor growth. Additionally, tumors develop mechanisms to suppress local immune reactions, such as producing inhibitory molecules or inducing regulatory T cells.
Melanoma and renal cell cancer tend to have a significantly higher number of mutations compared to most other cancer types, often due to carcinogen exposure (UV light for melanoma). This higher mutational burden increases the likelihood of producing immunogenic neoantigens that the immune system can recognize and respond to when stimulated by therapies like IL-2 or checkpoint inhibitors.
CAR T-cell therapy requires targeting a molecule on the cell surface that is unique to cancer and not present on normal cells. Such unique surface molecules for solid tumors have largely not been identified, and targeting molecules present even at low levels on normal cells can lead to severe, even fatal, side effects.
13 Actionable Insights
1. Cultivate Purpose to Alleviate Suffering
Develop an almost spiritual desire to become a doctor and do research, focusing on making progress in helping people and alleviating suffering rather than causing it.
2. Maintain Unwavering Life Focus
Once a core purpose is identified, stick with it diligently throughout your education and career to achieve your long-term goals.
3. Innovate, Create Tomorrow’s Medicine
From the outset of your career, aim to create the medicine of tomorrow rather than merely practicing today’s science or medicine.
4. Acquire Broad Foundational Knowledge
To avoid intimidation by the unknown and effectively tackle diverse scientific problems, acquire a broad background in foundational sciences like physical chemistry, quantum mechanics, and thermodynamics.
5. Seek Inspiring, Knowledgeable Mentors
To foster a good education and personal growth, surround yourself with people who possess extensive knowledge and can inspire you.
6. Commit to Tireless Work Ethic
To achieve significant progress, commit to working tirelessly and consistently, including weekends, often being present in your workplace almost every day.
7. Sustain Enthusiasm Despite Failures
Embrace the philosophy that success involves moving from failure to failure without losing enthusiasm, always maintaining belief that your efforts will eventually work.
8. Secure Strong Family Support
To sustain a high level of professional commitment, secure strong personal and family support that understands your work and actively helps by managing daily life burdens.
9. Practice Open Knowledge Sharing
Actively combat secrecy in science by openly sharing all knowledge, experimental results, and future plans with others to accelerate progress and help those suffering.
10. Persevere with Challenging Patients
Even when facing high rates of failure with critically ill patients, maintain a commitment to their care and use the profound suffering as motivation to work harder and innovate for improved treatments.
11. Appreciate Privilege of Helping
Acknowledge the unique and unbelievable privilege of being a doctor, using developed skills and wisdom to alleviate the suffering of others.
12. Read “The Transformed Cell”
For anyone wanting to understand how biomedical research is conducted, including the process of scientific discovery and the journey of failures and successes, read “The Transformed Cell” by Steve Rosenberg and John Barry.
13. Engage with Longevity Science Content
To translate the science of longevity into accessible knowledge, utilize Peter Attia’s podcast, website, and weekly newsletter.
6 Key Quotes
Success consists of moving from failure to failure without loss of enthusiasm.
Steve Rosenberg
Cancer is a holocaust. And it just seemed like the kind of thing I wanted to study.
Steve Rosenberg
It's the exquisite sensitivity and specificity of the immune reaction that I think makes it such a seductively interesting approach to trying to develop new cancer treatments.
Steve Rosenberg
Until you know it's possible, you never know that it's ever going to occur. And so that changed everything because it showed that simply administering this one molecule, a T-cell growth factor, could cause a cancer regression in a patient.
Steve Rosenberg
The bad news is, as you point out, it's going to have to be, as you target these mutations, highly individualized treatments.
Steve Rosenberg
If we could somehow overcome this secrecy that results from either people's own personal jealousies about wanting to be the one who does it, or intellectual property that companies have to protect to preserve themselves and raise funds to continue to do their work. We need kinds of regulations that will bring lawyers and doctors together to figure out ways to prevent that kind of secrecy from being a part of modern science. It's not like we're trying to create a better air conditioner. We're trying to save the life of another human being.
Steve Rosenberg
1 Protocols
Tumor Infiltrating Lymphocyte (TIL) Therapy for Metastatic Melanoma (with lymphodepletion)
Steve Rosenberg- Harvest tumor infiltrating lymphocytes (TIL) from the patient's tumor.
- Grow TIL cells to large numbers in vitro using interleukin-2 (IL-2).
- Temporarily eliminate the patient's natural inhibitory T cells and regulatory cells (lymphodepletion).
- Administer the expanded TIL cells intravenously to the patient.