Peter Attia MD177 - The development of cancer immunotherapy and its promise for treating advanced cancers
CHAPTERS
- 0:02 – 3:24
Childhood in the Bronx and the Drive to Become a Researcher-Physician
Peter Attia asks about Steve Rosenberg's early life. Rosenberg describes how the Holocaust news of his childhood inspired a spiritual desire to become a doctor and researcher who alleviates suffering, and a wish to create tomorrow's medicine.
- •Born in the Bronx; wanted to be a cowboy until age five or six
- •Postcards about relatives lost in the death camps motivated his wish to relieve suffering
- •Kept scrapbooks on medicine and research from a young age
- •Aimed to create the medicine of tomorrow rather than just practice today's
- 3:24 – 11:59
Training at Hopkins, Harvard PhD in Biophysics, and Mentor Frannie Moore
Rosenberg describes the six-year program at Hopkins, his choice to pursue a biophysics PhD to avoid being intimidated by any science, and his long surgical residency at the Brigham. He discusses his mentor Frannie Moore and the record 11 years it took him to finish.
- •Six-year combined college and medical program at Hopkins
- •Biophysics PhD chosen for broad scientific grounding
- •Took four years off after internship, which was unusual
- •Frannie Moore was respected more than loved and eventually supported his path
- •Residency took 11 years, a record at the Brigham
- 11:59 – 19:52
Two Early Patients That Planted the Seed of Immunotherapy
Rosenberg recounts a VA patient whose widespread stomach cancer disappeared spontaneously, and a kidney transplant recipient whose cancer regressed when immunosuppression was stopped. Both suggested the immune system could reject cancer. He also describes how little was known about tumor immunology at the time.
- •A patient's metastatic gastric cancer vanished without therapy over 12 years
- •A naive blood transfusion experiment to another patient failed
- •A transplant recipient's donor-derived renal cancer regressed after immunosuppression was withdrawn
- •In the early 1970s there were no known cancer antigens and immunotherapy was a dream
- 19:52 – 25:42
Becoming Chief of Surgery at the NCI
Rosenberg explains how he was appointed Chief of Surgery at the National Cancer Institute the day after finishing his residency, despite a tentative Dana-Farber offer. He recounts Frannie Moore's reaction and why he was committed to studying cancer.
- •Appointed NCI Chief of Surgery on July 1, 1974, a post he still holds
- •Had tentatively accepted a position at the new Dana-Farber
- •Moore refused to shake his hand when he left
- •Described cancer as a holocaust, linking it to his childhood motivation
- •The National Cancer Act had little effect on his intramural work
- 25:42 – 30:56
Early Research Agenda and the Naive First Experiments
Rosenberg describes surveying the existing cancer treatments of surgery, radiation and chemotherapy and wanting something bigger. He recounts early experiments, including the mini pig lymphocytes, and how the discovery of T cell growth factor opened the door to growing lymphocytes outside the body.
- •Surgery, radiation and chemotherapy produced only small incremental advances
- •Lymphocytes could not be kept alive outside the body in 1974
- •Mini pig lymphocyte experiments in six patients did nothing
- •Added to Pasteur: chance favors the prepared mind only if the mind is at work
- •T cell growth factor (interleukin-2) discovered in 1976
- 30:56 – 37:51
What Cancer Is and Why Metastatic Disease Is So Deadly
Rosenberg defines cancer by uncontrolled growth and the ability to spread, caused by accumulated mutations. He explains that epithelial tumors cause 90% of cancer deaths and that metastatic solid cancers are essentially incurable apart from a few exceptions.
- •Two defining properties: uncontrolled growth and ability to spread
- •Mutations accumulate as cells divide
- •Surgery cures over half of localized solid cancers
- •Metastatic disease is the dirty little secret of oncology
- •Exceptions: choriocarcinoma, germ cell tumors, and later melanoma and renal cancer with interleukin-2
- 37:51 – 43:01
Limits of Chemotherapy and the Promise of Immune Selectivity
The discussion covers how modern treatments extend survival by months at great cost and toxicity. Attia notes the real challenge of chemotherapy is selectively killing cancer cells, and Rosenberg says immunotherapy's selectivity is what makes it attractive.
- •Median survival in metastatic colorectal cancer rose from about 8–10 months to two and a half years
- •Many drugs add only weeks or months at enormous expense
- •Killing cancer cells is easy; sparing normal cells is hard
- •The immune system can recognize single amino acid changes
- 43:01 – 52:02
How the Immune System Works and Why Cancer Escapes It
Rosenberg explains how lymphocytes recognize viral antigens and form lasting immunity. He then addresses why tumors with mutations persist: weak immune responses and suppressive molecules and cells, with checkpoint modulators and IL-2 acting on the balance.
- •Lymphocytes patrol the body and respond to foreign antigens
- •Antigens are molecules recognized by T or B cells
- •Mutation-reactive cells exist in about 80% of common epithelial cancers but are weak
- •Tumors produce TGF-beta, IL-10 and recruit regulatory cells
- •Treatments can stimulate the immune system or release its brakes
- 52:02 – 1:04:58
Interleukin-2 and the First Durable Regressions in 1984
Rosenberg describes LAK cells being a false alarm, then more than 70 failed patients before an altered high-dose IL-2 schedule produced a melanoma regression in 1984. He discusses persevering through failures and the family support, especially his wife Alice, that made it possible.
- •LAK cells worked only on tiny tumors in mice
- •IL-2 had a seven-minute half-life, requiring a changed schedule and higher doses
- •First responder was a melanoma patient still disease-free over 35 years later
- •Response rates in melanoma and kidney cancer were about 15–20%, with a third complete and durable
- •Intuition, Lincoln's quote on failure, and Alice's support sustained him
- 1:04:58 – 1:18:09
Mutations, Neoantigens, and Why Treatment Must Be Individualized
Rosenberg explains that melanoma and kidney cancer responded because of high mutation burden, and that only about 1.5–2% of mutations are immunogenic given a patient's HLA type. Nearly every patient recognizes unique antigens, which is good news for broad applicability but means treatments must be individualized.
- •Melanoma and lung cancer have about 400 mutations per tumor; common cancers around 110
- •Driver mutations like P53 and KRAS are rarely recognized
- •Only 1.3–2.1% of mutations are immunogenic via HLA presentation
- •In 195 patients, about 80% had recognized antigens and virtually all were unique
- •Checkpoint modulators have little effect on most solid epithelial cancers
- 1:18:09 – 1:30:08
The Story of CAR T Cells, from NCI Lab to Kite and Gilead
Rosenberg explains how chimeric antigen receptors give T cells antibody-based recognition, and how targeting CD19 produced regressions in lymphoma. He recounts the first patient in 2009, the CRADA with Kite, and the sale to Gilead, then explains why CAR T cells do not work in solid tumors.
- •CAR T cells combine antibody recognition with T cell function
- •CD19 is expressed on normal B cells and B-cell cancers, and patients can live without B cells
- •First CAR T patient treated in 2009 remains disease-free
- •Kite Pharma formed a CRADA in 2012 and was sold to Gilead for $11.9 billion in 2017
- •Few cancer-unique surface molecules exist, so solid tumors remain out of reach
- 1:30:08 – 1:38:40
Tumor-Infiltrating Lymphocytes, Gene Transfer, and Mutation-Targeted T Cells
Rosenberg describes growing TIL from melanoma tumors, raising response rates to 30–35%, and the first gene transfer into humans using a marker gene after lengthy regulatory review. He traces how this led to improved TIL protocols and T cells targeting unique mutations, including the cholangiocarcinoma patient treated in 2014.
- •TIL gave response rates of 30–35%, but initially not durable
- •First gene insertion into human cells used a bacterial marker gene, after RAC review and lawsuits
- •Depleting regulatory T cells raised melanoma response to 55%
- •Mutation-targeted TIL gave a durable regression in a bile duct cancer patient
- •Responses were also seen in cervical, colon and breast cancers
- 1:38:40 – 1:46:25
Treating President Reagan and Turning Down Job Offers
Rosenberg explains how he came to join the team operating on President Reagan's colon cancer, and the press conference where he said the president had cancer despite Nancy Reagan's objection. He also explains the offers from Georgetown, Hopkins and the Brigham that he declined to stay in the lab.
- •Called to Bethesda Naval Hospital because he was nearby and had security clearance
- •He insisted on telling the truth that the president had cancer
- •He believes his word choice removed him from the shortlist for NCI director
- •Turned down Georgetown, Hopkins and Brigham to avoid administrative roles
- •Wanted to stay in the lab and mentor fellows
- 1:46:25 – 1:56:18
Checkpoint Inhibitors and the Path to Curing Solid Cancers
Rosenberg explains how checkpoint antibodies release brakes on lymphocytes, working mainly in high-mutation cancers. Asked whether adoptive cell therapy is the way forward, he expresses strong confidence that engineered or selected T cells targeting individual mutations can treat common solid cancers.
- •Checkpoint antibodies take the brakes off T cells rather than killing cells
- •They work best in high-mutation cancers like melanoma and MSI tumors
- •Most common epithelial cancers respond little
- •T cell receptors against P53 and KRAS have been cloned, making it nearly an engineering problem
- •Rosenberg says his intuition is very strong that it will work and it is all he is working on
- 1:56:18 – 2:11:33
Openness in Science and the Human Side of Caring for Cancer Patients
Attia recalls lessons from working with Rosenberg: no secrecy and never retreating from the bedside. Rosenberg criticizes secrecy in medicine and discusses carrying the burden of patients who die, and the two share personal reflections and thanks.
- •Fellows in Rosenberg's lab are told to share everything they know
- •Rosenberg objects to secrecy driven by jealousy and intellectual property protection
- •Most NCI patients have exhausted standard therapies, and most do not survive
- •Rosenberg says he thinks of the tragedies at night, and that doing everything he reasonably can eases the burden
- •Attia expresses deep gratitude for Rosenberg's influence
