ACGT September 2026 Research Roundup.

September’s ACGT Research Roundup highlights immunosenescence in CAR T-cell products, the first phase 3 win for an individualized neoantigen therapy, and more.

Joseph A. Fraietta, PhD (University of Pennsylvania), led a study asking why CAR T-cell therapy is often less effective for patients with chronic lymphocytic leukemia, and found that by the time they report for duty, the immune cells are already aged. T cells from patients who responded were often worn out at the time of collection, and CAR T cells manufactured from untreated samples showed hallmarks of cellular senescence. Those products hit a ceiling on how much they could multiply, and the most senescent cells lost their killing capacity. Ibrutinib treatment improved the cells’ fitness and boosted expansion, pointing to something clinicians may be able to measure ahead of time and act on. Fraietta’s co-authors included UPenn colleagues Carl H. June, MD, Bruce L. Levine, PhD, and Daniel J. Powell Jr., PhD, along with Marcela V. Maus, MD, PhD (Mass General Brigham Cancer Institute). This research was published in Blood.

E. Antonio Chiocca, MD, PhD (Mass General Brigham) and colleagues described how a common mutation in high-grade brain tumors leaves them unusually vulnerable to an oncolytic herpes virus. The IDH1-R132H mutation leads to two consequences: it raises levels of NECTIN-1, the main doorway HSV-1 uses to enter glioma cells, and it dials down the tumor’s own antiviral defenses. Across patient tumors, NECTIN-1 was the only viral entry receptor enriched in IDH-mutant grade 3 astrocytomas, suggesting a vulnerability specific to HSV-1 rather than to oncolytic viruses in general. Tumors were also shown to resist by engaging the TIGIT checkpoint in infiltrating immune cells. Pairing the virus with TIGIT blockade has been shown to extend survival and produce lasting immune memory in mice, while PD-1 blockade showed no benefit. This commentary was published in Molecular Therapy: Oncology.

• Joseph A. Fraietta, PhD, Carl H. June, MD, and Bruce L. Levine, PhD (UPenn) were featured in The Daily Pennsylvanian’s two-part series on CAR T-cell therapy at UPenn. The first installment traced June’s path to the technology, which began not with cancer but with bone marrow transplantation research and then HIV work at the Naval Medical Research Institute. The second installment turned to solid tumors, where Fraietta described the tumor microenvironment as a “sewer” that CAR T cells must function inside. The editorial also covered fibroblast-targeting CAR T cells, in vivo CAR generation, and imaging to track where infused CAR T cells go post-infusion.
• Stephen Gottschalk, MD (St. Jude Children’s Research Hospital) and colleagues improved CAR T-cell therapy for osteosarcoma by cutting a brake line in CAR T cells, by deleting the Regnase-1 gene that restrains immune function.  Nearly all treated mice survived, and an early-phase clinical trial is in development. This research was published in Cell Reports Medicine.
• Carl H. June, MD (UPenn) and Crystal Mackall, MD (Stanford University) were featured in an American Association for Cancer Research (AACR) Cancer Research Catalyst blog about the current state of the CAR T-cell therapy field.
• Alexander Marson, MD, PhD (Gladstone-UCSF Institute of Genomic Immunology) was featured in an article by the Gladstone Institutes that explored how Marson’s team built a reference manual for how genes control human T cells by mapping the circuits connecting them. “We now have a fundamental rulebook of how genes control T cell responses,” Marson said, adding that the hope is for it to become a lookup table any scientist can consult. This work was published in Cell.

• Chien-Fu Hung, PhD (Johns Hopkins University) and colleagues published two papers on therapeutic HPV vaccines. The first identified a DNA vaccine construct that combined a cell-penetrating peptide with a signal sequence to drive strong antitumor responses in mice; the second paired a bacterial vesicle-based vaccine with an immune-stimulating Flt3L therapy. These articles were published in Obstetrics and Gynecology Research and Vaccines.
• Maciej S. Lesniak, MD (Northwestern University) and colleagues examined how chemokine signaling shapes glioblastoma, arguing that known genetic drivers do not fully explain how tumor cells adapt to hostile surroundings. In their view, chemokines act less as oncogenic drivers than as regulators responding to location and stress. The authors published this review in the Journal of Neuro-Oncology.
• Alexander Marson, MD, PhD (Gladstone-UCSF Institute of Genomic Immunology) and colleagues developed a toolkit for engineering myeloid cells, which hold promise for immunotherapy but are hard to engineer at scale, using virus-like particles that deliver CRISPR editing into these cells while keeping them alive and immunologically responsive. This research was published in Nature Biotechnology.
• Ira Mellman, PhD (Parker Institute for Cancer Immunotherapy and Medici Therapeutics) and colleagues argued that cancer immunotherapy needs to return to first principles. Progress has slowed as efforts concentrated on reproducing the success of PD-(L)1 blockade, a pattern the authors say signals the need for a deeper understanding of human cancer immunity. This perspective was published in Nature Reviews Immunology.
• Katy Rezvani, MD, PhD (The University of Texas MD Anderson Cancer Center) and colleagues examined a study explaining why natural killer cells lose their cancer-killing ability inside glioblastoma. Removing one component of the cells’ mitochondrial machinery, NDUFA9, stripped them of antitumor activity, while restoring it restored that function. This commentary was published in Cancer Discovery.
• Michel Sadelain, MD, PhD (Columbia University) found evidence that TNF produced early by CAR T cells is upstream of the inflammatory cascade associated with severe CRS. In experimental models, disrupting TNF signaling altered the subsequent macrophage/inflammatory response. This research was published in Science Immunology.
• Sheila K. Singh, MD, PhD (King’s College London) and colleagues published a method for culturing group 4 medulloblastoma cells, which are notoriously hard to keep alive in the lab. The protocol runs from resected patient tumor through mouse engraftment to short-term culture, which provides enough time for drug screening. This protocol was published in STAR Protocols.
• Ben Z. Stanger, MD, PhD (University of Pennsylvania) and colleagues tested CA19-9 — the marker oncologists already use to track pancreatic cancer — as a CAR T-cell target. Their screening of 14 designs identified one that cleared pancreatic tumors and metastases in mice and also controlled colon, bile duct, gastric, and esophageal tumors carrying the marker. This research was published in Gastroenterology.

• FDA Launches Expedited IND Pilot, Begins Accepting Applications. The U.S. Food and Drug Administration announced the final design of the Expedited Investigational New Drug (IND) Pilot to accelerate clinical trial timelines and reduce regulatory hurdles, helping maintain American leadership in global medical innovation.
• IND Application Accepted, Phase 1 Clinical Trial Launched for New In Vivo CAR T-cell Therapy. The FDA has cleared Vyriad’s IND application for VV169, an off-the-shelf CAR T-cell therapy targeting BCMA in relapsed/refractory multiple myeloma. Instead of engineering a patient’s T cells in a lab, VV169 is designed to create CAR T cells directly inside the body, avoiding the weeks-long manufacturing wait. The Phase 1 trial is now enrolling up to 40 patients at Mayo Clinic.
• GPC3 CAR T produces complete regression in a young child with liver cancer. A 3-year-old with chemotherapy-resistant metastatic hepatoblastoma, the most common pediatric liver cancer, had complete tumor regression lasting at least 12 months after treatment with GPC3-targeted CAR T cells expressing IL-15 and IL-21. The results come from a report by researchers at Texas Children’s, Baylor College of Medicine, and Seattle Children’s.
• EGFR-targeted CAR T produces a reported complete response in metastatic anal cancer. A2 Biotherapeutics, a clinical-stage immunotherapy company developing first-in-class logic-gated therapies for solid tumors, announced early safety and efficacy data from the ongoing DENALI-1 clinical study (NCT06682793). The findings include the first reported complete response (CR) in a patient with metastatic anal cancer.
• CAR T-cell therapy against a new myeloma target succeeds in pivotal trial. Bristol Myers Squibb’s arlo-cel, a one-time CAR T-cell therapy aimed at GPRC5D, met its main goal of overall response rate in patients with multiple myeloma who had already tried four types of treatment, including a BCMA-targeted therapy. It also met its key secondary goal of complete response rate. BMS has not yet released any data and plans to present results at an upcoming medical meeting.
• First phase clinical trial 3 success for a personalized mRNA cancer therapy. Merck and Moderna reported on August 19 that intismeran autogene, an mRNA therapy tailored to each patient’s tumor mutations, kept melanoma from returning longer than Keytruda alone in more than 1,100 patients with stage IIB-IV disease that had been surgically removed. It is the first phase 3 trial with an individualized neoantigen therapy to achieve its endpoint. 
• CREATE Medicines and WestGene partner on in vivo CAR therapies. In vivo CAR therapy skips the manufacturing step, using lipid nanoparticles to reprogram immune cells inside the body. CREATE will pair its platform with WestGene Biopharma’s targeted delivery technology to advance three programs, including one aimed at HER2 and TROP2 in solid tumors. 
• CAR T cells can drive treatment-resistant rheumatoid arthritis into remission. Six patients at Charité – Universitätsmedizin Berlin whose severe disease had failed as many as eight prior therapies received CD19-targeted CAR T cells, the same approach used against B-cell blood cancers. Disease activity fell sharply in all six, and three stayed in remission with no arthritis medication for up to a year. 
• Do supercentenarians’ immune systems explain their longevity? Researchers at the University of Osaka examined blood from people ranging from their 70s to past 110 and found a rare type of CD4+ T cell that multiplies rather than fades after ten decades of life. These cells can kill infected and cancerous cells, and in the oldest donors a few had grown into large clonal populations whose T-cell receptors matched receptors found in patients with lung, breast, and liver cancer, even though none of the donors had ever been diagnosed with those diseases. The researchers suspect these cells may be quietly catching cancer early, but stress that is a possibility their study raises, not one it proves.