Engineering T cells for immunotherapy vs cancer had already had marked success in certain types. But there's a next generation in the hopper, as reviewed today @Cancer_Cell, that ought to help take the field much further into solid tumors

Tomorrow at #ESMO26#: MSK hepatopancreatobiliary surgeon Dr. Vinod Balachandran (@TheVinodLab) will discuss immunotherapy in pancreatic cancer and overcoming barriers to success. 🗓️ Monday, October 26 | 11:15 a.m. CET

Last month Moderna reported the first individualized cancer vaccine to pass a Phase 3. Moderna CEO Stéphane Bancel and a16z's Jorge Conde on what that actually means: The treatment works by sequencing a patient’s tumor and healthy cells, identifying the mutations relevant to their cancer, and encoding up to 34 of them into an mRNA specific to the individual. Rather than simply unleashing the immune system, the goal is to teach it what to recognize and attack. In this conversation, they unpack the engineering challenge of manufacturing a different medicine for every patient, how Moderna has brought the process down to roughly 42 days from biopsy to treatment, and what it would take to manufacture personalized medicines at scale. 00:00 Intro 02:35 A Phase 3 that beat the standard of care 06:00 Why today's immunotherapy fails 40% of patients 09:35 A vaccine for cancer you already have 11:20 Why mRNA worked where 1,000 trials failed 13:15 90% of cancer antigens are unique to you 16:35 Why this vaccine only gets better from here 21:00 The only thing Moderna needs is your DNA sequence 22:20 Why the first robot was intentionally inefficient 27:10 How the FDA approves a drug that's different every time 33:05 A cancer treatment with the side effects of a flu shot 33:30 Why pancreatic cancer is worth a risk 36:30 Rare liver disease next, then autoimmune YouTube: @moderna_tx @JorgeCondeBio

🚨 NEST is a big deal, and now fully published. 24 patients with localized CRC. BOT + BAL (CTLA4 + PD1) before surgery. 60% with major responses. We’ve been inching toward neoadjuvant therapy in colon cancer for years. FOxTROT tried it with chemotherapy and showed there was something there. NICHE then showed us that neoadjuvant immunotherapy can be wildly effective in dMMR/MSI-H colon cancer (I'm still pushing to rename this to Chalabi's disease). The real question has always been: can we make this work in pMMR/MSS disease? NEST says yes. Among the 22 pMMR tumors: 🔥 41% major pathologic response 🔥 32% pCR 🔥 59% had ≥50% tumor regression And no treatment-related delays to surgery. Chalabi's tumors (dMMR)? 100% MPR. It’s only a phase II, but a 32% pCR rate in pMMR colon cancer with immunotherapy is kind of insane. NEST is telling us MSS is be coming through the IO door next. And now we have ROBBIN (the phase III) coming. Get ready. Neoadjuvant therapy is going to become a much bigger part of how we treat colon cancer. This is where CRC is going. 🧬🔥 @OncoAlert @oncodaily @Onco_Nexus @TheGutOncLab

Hear me out. On paper COMMIT is a "Positive" trial. It is also a spectacular demonstration that Atezolizumab monotherapy should never be used for metastatic MSI-H CRC (we can talk about adjuvant). COMMIT was a randomized first-line study in metastatic MSI-H/dMMR CRC. It began as a 3-arm trial of: • mFOLFOX6/bevacizumab (this sucks) • atezolizumab alone • mFOLFOX6/bevacizumab/atezolizumab After KEYNOTE-177 changed the standard of care, the chemotherapy-only arm closed after 20 patients. The trial continued with 82 patients randomized between atezo alone and the four-drug combination. The headline is that adding FOLFOX/bevacizumab to atezo improved PFS: HR 0.42 Median PFS: 24.5 vs 5.3 months ORR: 86% vs 46% Primary progression: 2.8% vs 32.4% The truth is Atezolizumab PALES in comparison to its contemporary PD1/PDL1 agents in this setting. Single-agent atezo: 12-month PFS 35% 24-month PFS 32% For comparison: Pembrolizumab in KEYNOTE-177: 12-month PFS 55% 24-month PFS 48% Nivolumab in CheckMate 8HW: 12-month PFS 63% 24-month PFS 56% This is not evidence that every patient with metastatic MSI-H CRC needs chemotherapy, bevacizumab, and immunotherapy. It is evidence that NO ONE SHOULD BE USING ATEZOLIZUMAB IN METASTATIC MSI-H CRC. And now, drumroll please… The only positive randomized adjuvant immunotherapy strategy in stage III dMMR colon cancer is ATOMIC: FOLFOX + atezolizumab. That makes COMMIT more than a roast. It raises a important question about ATOMIC. Should we be using Atezolizumab in the adjuvant setting? Do we need to be giving chemotherapy here? Looking forward to what others make of this but this is the real question. @TheGutOncLab @OncoAlert @oncodaily

How often does a company stop an actively enrolling global phase III trial and open an entirely new registration study? Well, it happened last week. Agenus is moving from BATTMAN to ROBBIN (which certainly has some ethical implications for starting/stopping a study I won't comment on). BATTMAN was testing BOT/BAL against best supportive care in refractory MSS metastatic colorectal cancer. An important question, but a best supportive care control was never likely to gain traction in the United States. ROBBIN moves BOT/BAL where it may have its best chance to work: previously untreated, high-risk stage II/III MSS colon cancer, before surgery and while the primary tumor remains intact. The rationale borrows from FOxTROT and builds on early neoadjuvant immunotherapy work from MSK and others like @pashtoonkasi . The early BOT/BAL data are compelling: • Pathologic response in approximately 60–70% • Major pathologic response in ~35–40% • pCR in ~30% Those are extraordinary numbers for MSS colon cancer and outperform the chemotherapy experience from FOxTROT. ROBBIN will randomize 850 patients to short-course neoadjuvant BOT/BAL followed by standard care versus standard care alone, with event-free survival as the primary endpoint. Will the pathologic responses translate into fewer recurrences? I think there is a real chance they will. The tradeoff will be toxicity. Grade 3 colitis/diarrhea occurred in 13% in one of the early cohorts, although there were no grade 4 events and almost no impact on surgical timing. So yes, you can still smell the colitis. But it may be worth it. @TheGutOncLab @Onco_Nexus @oncodaily @OncoAlert