a16zInside Moderna’s Biggest mRNA Test Since COVID
a16z
A First Working Cancer Vaccine 0:00
Moderna and Merck announced that a phase three clinical trial in melanoma met its primary goal, showing a treatment that works better than the immunotherapy drug Keytruda alone. Stephane Bancel, Moderna's CEO, explains that the cancer vaccine field has run more than a thousand clinical trials over twenty years, all of which failed until now. The trial measured recurrence free survival, meaning whether the cancer came back or the patient died, and it also unexpectedly met a harder secondary goal called distant metastasis free survival, which tracks whether the cancer spread to other parts of the body. Earlier phase two data presented at the ASCO oncology conference in spring 2026 showed that around 80 percent of treated patients were disease free five years after treatment and surgery, compared to a lower rate for Keytruda alone. Bancel says the manufacturing site in Massachusetts is ready, and the company hopes to make the treatment available to patients as soon as 2027.
Why Keytruda Alone Falls Short 6:02
Keytruda works by releasing the body's own immune cells to attack cancer, something Bancel compares to opening the gates and letting the dogs out. When it works, patients can be effectively cured, but only about 60 percent of people remain disease free five years after treatment, according to published phase three data. The other 40 percent go through treatment without benefit, and immunotherapy drugs like this often cause serious autoimmune side effects such as type 1 diabetes, lupus, or Crohn's disease, since they activate the immune system broadly rather than precisely. Moderna partnered with Merck back in 2015 and 2016 to build something different: a treatment that starts from the sequence of a patient's own tumor, so instead of releasing the immune system's dogs randomly, it teaches them exactly what to look for.
Calling It a Vaccine 9:31
Although patients already have cancer, the field uses the word vaccine because the treatment teaches the immune system, the same basic idea behind a flu or COVID shot. The difference is that instead of preparing the body for a virus, it prepares the body for a cancer signal the immune system already missed. Bancel explains that everyone has cancer cells in their body regularly, formed through normal cell replication errors, and the immune system usually catches and eliminates them early. Cancer becomes a problem when it grows past that natural defense, and the vaccine's job is to retrain the immune system to notice it again.
What Made This Attempt Different 11:30
Two things set this effort apart from decades of failed trials. First, Moderna's mRNA, once injected into muscle, travels to the lymph nodes and enters antigen presenting cells, key immune cells, where it is translated and displayed from within, unlike older cancer vaccines made from proteins or peptides that simply circulate in the blood without that internal presentation. Second, the treatment is built individually for each patient. Because cancer is fundamentally a disease of DNA, and DNA sequencing has become far cheaper over the past twenty years, Moderna sequences a biopsy of the tumor and a healthy cell from the same patient, compares them letter by letter, and uses an algorithm to select the 34 most relevant mutations. These are stitched into a single mRNA molecule made in about 30 days and injected in a hospital. Research at ASCO and in the phase two study found that around 90 percent of these mutations differ from one patient to another, meaning individualization, not a shared vaccine, is the only way this approach works.
Building and Improving the Algorithm 15:03
The algorithm that selects the 34 mutations draws on published research, internal data built up over years, and partnerships with diagnostics and cell therapy companies that provided T cell mapping data. Bancel calls the current version "Instrin 1.0," noting it has been essentially the same since phase one, phase two, and phase three, even as results improved through learning. With phase three patient samples now available, Moderna plans to study why roughly 20 percent of patients still do not respond, hoping to refine the algorithm toward a future 2.0 version, always working with regulators to avoid losing effectiveness. He compares it to artificial intelligence, saying today's version of this technology is the worst version the field will ever see again, which raises hope both for the remaining melanoma patients and for harder cancers like pancreatic cancer where immunotherapy has struggled.
Manufacturing One Vaccine Per Patient 18:31
Unlike CAR-T cell therapy, which removes and reprograms a patient's own immune cells in a lab before returning them to the body, Moderna's process only needs information: the genetic sequence of a patient's healthy and cancerous cells. From that file, the company synthesizes DNA and RNA enzymatically in water rather than growing it in large bioreactors, making the process closer to small molecule manufacturing than to cell therapy. The full needle to needle time, from biopsy to injection, currently runs about 42 days, with room to shrink further through automation and robotics. Early machines were built for quality and reliability rather than efficiency, since a flawed but promising treatment could have wasted years if manufacturing problems produced false negative trial results. Once the phase two data confirmed the science worked, engineers shifted focus to compressing manufacturing volume and cycle time, since a smaller physical footprint allows more machines per clean room and lowers fixed costs. The existing facility in Marlborough, Massachusetts already produces thousands of doses for nine ongoing clinical studies and is expected to scale to tens of thousands of doses annually, enough to cover the melanoma market, with pricing and cost details still undisclosed pending discussions with payers.
Personalization and Future Regulation 25:30
Bancel expects most patients seeking individualized treatments to come through Moderna rather than pursue one-off personal efforts, since an industrialized, validated process carries far less risk of contamination or manufacturing error than a bespoke approach. He compares it to making your own knife out of necessity versus buying one from a shop once high quality manufacturing exists. On regulation, he notes there is precedent in CAR-T therapy, which was approved as a process, not as a single fixed product. Moderna expects its cancer treatment to be regulated the same way, as a process approval covering the entire manufacturing and algorithmic system rather than approving each individually different dose on its own.
Years of FDA groundwork 28:00
The regulatory pathway for this individualized cancer treatment has been built over roughly a decade of conversations with the FDA, starting with the process IND needed just to enter the clinic. Before every phase three trial, the company has held end of phase two meetings to agree on trial design and manufacturing protocols, and it has requested extra meetings to walk regulators through the technology. The core question the FDA needs answered is whether the same starting sample, taken from a patient's tumor and blood, reliably produces the same individualized product at the end of the manufacturing process, and proving that consistency is the central task ahead.
Proof of new T cells 30:00
Blood samples taken before and after treatment in melanoma patients showed something new: rather than just expanding existing T cells, the therapy created brand new T cells that recognize targets encoded in the mRNA, targets the immune system had not responded to before. This is taken as proof that the platform can teach the immune system to build fresh defenses against cancer.
Three paths beyond melanoma 31:00
Expansion beyond melanoma follows three directions. First, wherever Keytruda already works, including ongoing phase three lung cancer trials and phase two kidney and bladder cancer trials, since the two mechanisms are believed to work in complementary ways. Second, catching disease early, illustrated by a planned 2026 phase three trial for stage one lung cancer using the mRNA treatment alone, without a checkpoint inhibitor, since checkpoints carry serious lifelong autoimmune side effects that doctors avoid using at that early stage; screening former smokers regularly with X-ray is floated as a practical way to catch tumors early enough for surgery plus this lower-side-effect treatment. Third, cancers such as pancreatic and gastric cancer where checkpoints and Keytruda have historically failed, with a possibility of eventually combining this approach with newer drugs like the recently approved KRAS-targeting pancreatic cancer medicine from Revolution Medicines.
Learning from non-responders 35:00
Because this is still an early version of the technology, the team plans to use AI to study the roughly 20 percent of patients who do not respond even five years out, in order to understand why and see if the algorithm or technology can be adjusted to help them.
New frontiers: rare disease, autoimmunity 36:00
Before the end of the year, a pivotal late-stage study is expected for a rare genetic liver disease in children, where early trial data has shown kids doing well three years on the drug. The company also announced in June that its next major target is autoimmune disease, aiming to treat root causes rather than just symptoms, using knowledge gained from infectious disease and cancer work. Two approaches are being pursued: a standardized product for everyone, and, still in the lab, an individualized treatment that would direct part of a patient's own immune system to attack the specific immune cells causing the autoimmune attack.
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