Avoiding, Treating & Curing Cancer With the Immune System | Dr. Alex Marson

What It Covers

Dr. Alex Marson, physician-scientist at UCSF, explains how the immune system's T cells and B cells function, how cancerous mutations accumulate over time, and how CRISPR-engineered CAR T cells are moving from experimental trials into approved treatments. The episode covers cancer risk factors, checkpoint inhibitor immunotherapy, lipid nanoparticle delivery systems, and the current state of gene-editing clinical trials for solid tumors.

Key Questions Answered

• •CAR T Cell Therapy: Chimeric antigen receptor T cells are lab-designed receptors that do not exist in nature, inserted into a patient's own extracted T cells via lentivirus or electroporation, then reinfused like a blood transfusion. These engineered cells seek and destroy specific cancer targets. Emily Whitehead, an eight-year-old with treatment-resistant leukemia in 2012, became the first pediatric patient cured using this approach and is now pre-med at the University of Pennsylvania.
• •CRISPR Precision Editing: CRISPR-Cas9 uses a guide RNA molecule to direct a protein scissor to any targeted DNA sequence. Researchers order the RNA online, mix it with Cas9 protein, and electroporate T cells within days. Marson's lab, in collaboration with Jennifer Doudna, pioneered this in primary human T cells. Arsenal Biosciences, a company Marson co-founded, now runs clinical trials inserting up to 10,000 nucleotides of custom DNA code into T cells for solid tumors including prostate cancer.
• •Cancer Risk Accumulation: Cancer risk rises with age because each cell division introduces imperfect DNA replication, and mutations accumulate probabilistically over decades. Most mutated cells trigger programmed cell death and die off harmlessly. However, a mutation that confers a growth advantage causes that cell to divide more, passing the mutation to daughter cells. Subsequent additional mutations can transform dividing cells into full cancers. Smoking, UV exposure, and pesticide contact accelerate this mutation rate significantly.
• •Checkpoint Inhibitors: PD-1 and CTLA-4 are natural brakes on T cells that cancer exploits to avoid immune destruction. Drugs that block these checkpoints remove the brakes, allowing existing T cells to attack tumors. Melanoma is the clearest success case — Jimmy Carter's brain-metastasized melanoma resolved after checkpoint inhibitor treatment, a result previously considered impossible. Not all cancers respond equally, and researchers are identifying which tumor types are most susceptible to this approach.
• •Lipid Nanoparticle Delivery: Lipid nanoparticles, the same fatty-bubble technology used in mRNA COVID vaccines, are now being engineered with surface proteins that bind specifically to T cells. Injected into the bloodstream, these particles deliver mRNA encoding CAR receptors directly to T cells without removing cells from the body. University of Pennsylvania researchers demonstrated functional CAR T cell generation in animal models using this entirely in-body method, potentially eliminating the need for centralized cell manufacturing facilities.
• •Autoimmunity Mechanism: Autoimmune diseases arise when T cells that escaped thymic negative selection — the process that eliminates cells recognizing self-tissue — evade secondary suppression mechanisms. When these cells activate, they attack specific tissues: joints in rheumatoid arthritis, insulin-producing pancreatic cells in type 1 diabetes, and myelin in multiple sclerosis. Therapeutic goals focus on targeted suppression of only the misdirected immune response rather than broad immunosuppression, which leaves patients vulnerable to infection.
• •Two-Factor Authentication for Tumor Targeting: A core challenge in CAR T therapy for solid tumors like pancreatic or brain cancer is collateral damage to healthy tissue sharing surface proteins with cancer cells. Researchers are engineering T cells to require simultaneous recognition of two distinct surface markers before killing a cell — analogous to two-factor authentication — so that neither marker alone triggers destruction. This combinatorial targeting approach reduces off-tumor toxicity and is being actively developed for cancers where single-target approaches cause unacceptable side effects.