Memorial Sloan Kettering Cancer Center (MSK) experts presented findings from their latest foundational and translational oncology research at the American Association for Cancer Research (AACR) Annual Meeting 2026, held April 17 to 22 in San Diego.
Highlights included treatment of early-stage rectal cancer with protein inhibitors targeting HER2, alleviating the need for some patients to receive radiation and/or surgery. Additional topics included the development of a personalized RNA vaccine for pancreatic cancer, with almost 90% of responders still alive six years after treatment, and development of a framework to understand biomarkers and vulnerabilities during the early to late stages of transitions from lung cancer-enabling adenomas to neuroendocrine lineage plasticity.
The summaries below highlight the breadth of oncology research at MSK as researchers investigate and define the most pressing questions in cancer.
Personalized RNA Vaccines for Pancreatic Cancer
Pancreatic cancer patients have a five-year average survival rate of 13%. The tumors are typically low-mutation, which makes them difficult to treat with immunotherapy, as they are often insensitive to first-generation immune checkpoint therapies. However, MSK research uncovered that some rare long-term pancreatic cancer survivors naturally mount CD8⁺ T cell responses against highly immunogenic mutation-derived proteins called neoantigens, paving the way for a new precision immunotherapy approach – cancer vaccines.
Vinod P. Balachandran, MD, hepatopancreatobiliary surgeon and director of The Olayan Center for Cancer Vaccines at MSK, presented long-term data from a phase 1 trial of personalized RNA neoantigen vaccines in pancreatic cancer. Of the 16 clinical trial participants who received the vaccine, half responded, mounting a robust, long-lived immune response (responders). Now six years later (median follow-up was 4.2 years), the researchers found that 87.5% of vaccine responders are still alive (n=7/8), compared to 25% (n=2/8) of the nonresponders (no vaccine-induced immune response). Responders’ median overall survival was not reached, while non-responders’ median overall survival was 3.4 years.
The research included deep longitudinal immunological analyses, allowing Dr. Balachandran and colleagues to identify mechanisms that may drive sustained, potentially clinically meaningful vaccine immunity. This research provides the first evidence that vaccines can induce robust, long-lasting immunity in a deadly, low-mutation cancer. Ultimately, the findings will guide new and improved ways to treat more patients with pancreatic cancer and other deadly cancers with these promising therapies.
Read AACR Abstract 324. Access disclosures for Dr. Balachandran. An ongoing multicenter phase 2 trial (Sponsor: Genentech/BioNTech) is testing this approach in a larger number of people. Explore MSK clinical trials for patients with pancreatic cancer.
Rectal adenocarcinoma: Utilizing targeted HER2-treatments to improve tumor responses and avoid surgery
Early-stage rectal cancer is conventionally treated with chemotherapy, radiation, and often surgery, all of which can cause multiple side effects, which are potentially permanent. To identify a less invasive and lower-burden treatment, gastrointestinal medical oncologist Michael Foote, MD, gastrointestinal medical oncologist Andrea Cercek, MD, gastrointestinal medical oncologist Luis Diaz Jr., MD, and their colleagues evaluated protein inhibitors targeting HER2 in patients with overexpressed HER2. Dr. Foote presented the early results from this phase 2 trial at AACR.
In this single-arm study with 10 patients, Dr. Foote and his colleagues treated patients who were diagnosed with RAS-wild-type, mismatch-repair-proficient, early-stage rectal cancer, with six weeks of induction HER2-targeted therapy: trastuzumab and tucatinib. The patients then continued trastuzumab and tucatinib for 15 weeks, adding FOLFOX or CAPOX chemotherapy. Nine of the patients completed the initial HER2-targeted therapy, and eight of the patients completed the full 21 weeks of neoadjuvant therapy.
After the initial six-week cycle of trastuzumab and tucatinib, 78% of patients (n=7/9) had significant shrinkage of their tumor mass. Eight patients completed the additional 15 weeks of combination therapy: four patients (50%) exhibited a complete clinical response (cCR) with tumor disappearance after the full 21 weeks of treatment. An additional patient, who received both induction and combination therapy, achieved a cCR with subsequent radiation. Researchers found that only patients with 3+ HER2 expression achieved a cCR.
Overall, 63% (n=5/8) of patients were able to avoid rectal surgery with this regimen as of the data cutoff, with a median 30 months of patient observation. Several patients experienced local regrowth of their tumor, but no patient required surgery for this growth. Recurrent tumors were managed with either radiation or a minor procedure. Encouraged by these interim results, Dr. Foote and colleagues will continue enrolling patients in the trial.
Read AACR Abstract. Access disclosures for Dr. Foote. Explore MSK clinical trials for patients with rectal cancer.
Stem-like intermediates and diverse trajectories of neuroendocrine plasticity in lung cancer
Lung cancers can evade targeted therapies by changing their identity, a process known as neuroendocrine (NE) lineage plasticity. In this process, lung adenocarcinomas (LUAD) can transform into more aggressive NE cancers, such as small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), which are harder to treat. However, how these transformations occur, and why some tumors follow different paths, has remained poorly understood. To address this, thoracic medical oncologist Joseph Minhow Chan, MD, PhD, a member of the Human Oncology and Pathogenesis Program, and his colleagues analyzed tumor samples using targeted DNA sequencing, 10X single-cell transcriptomics (75 samples, 52 patients), and Xenium spatial imaging (22 samples, 16 patients) across patients with NE-transformed lung cancers. Key findings include:
- Distinct genotypes can converge on shared mutational patterns and increased tumor diversity. Both EGFR-mutant and EGFR-wildtype transformed tumors exhibited high genomic instability and enrichment of PI3K/AKT pathway alterations. The end result revealed by scRNA-seq was substantial tumor subtype diversity compared to control samples, highlighting a clinically challenging scenario where multiple tumor states would need to be treated simultaneously.
- A shared intermediate state may drive transformation. By developing new computational tools based on time-series analysis (scDeBussy), the researchers identified a recurrent “basal-like” cell state that appears before transformation and is associated with multiple downstream fates, including NE, squamous, and mesenchymal lineages. This emphasizes the extent of tumor heterogeneity and could suggest a promising early biomarker for plasticity.
- The tumor microenvironment could shape these transitions. Spatial imaging showed that tumor subtypes are organized within the microenvironment, with patterns consistent with hypoxia and immune exclusion, suggesting that extrinsic factors may influence tumor evolution.
- PHOX2B promotes a NE-like state. Comparing transformed and de novo SCLC identified PHOX2B as a transcription factor strongly associated with NE cell states. In EGFR-mutant LUAD models, PHOX2B promoted NE features and suppressed dependence on EGFR signaling, further enhanced by REST suppression. While these changes were insufficient to induce full SCLC morphology, they were consistent with plasticity promoting EGFR independence.
- An alternative plasticity axis in STK11/KEAP1-mutant tumors. Researchers recognized STK11/KEAP1 co-mutations as an alternate route to NE plasticity in EGFR-wildtype tumors. These mutations were significantly enriched in the high-grade NE cancer LCNEC (28-31%), compared to LUAD or SCLC (10-11%, 1-4%). These tumors were enriched for an HNF1/4A-associated gene programs alongside NRF2-driven redox pathways, consistent with features of hepatic development and metabolic adaptation. Together, these findings point to a distinct NE-to-GI-like state in this subset of tumors.
Overall, this work suggests that histological transformation is not a single event, but a dynamic process that proceeds through shared intermediate states, with diverse evolutionary paths shaped by both genetic background and the tumor microenvironment. These findings provide a framework for understanding how cancers evolve resistance and may help guide future therapeutic strategies.
Read AACR Abstract 6797. Access disclosures for Dr. Chan. Explore MSK clinical trials for patients with lung cancer.