Research Roundups
ACGT August 2026 Research Roundup.
August’s ACGT Research Roundup highlights recent cell therapy trial results, more evidence of the incredible long-term persistence of CAR T cells in patients, challenges associated with CAR natural killer (NK) cells, and new approaches involving gamma delta T cells as well as an injectable microfoam to create CAR T cells in the body.
Designing better molecular anchors
Sidi Chen, PhD (Yale School of Medicine) led the development of DeepSCan, a suite of deep learning models that design molecular anchors to hold engineered antigens on the cell surface. These anchors are used in mRNA vaccines and cell therapies, but the optimal sequences remained unknown, so the team measured surface expression across more than 570 chimeric antigens, trained the models on those results, and then used them to design 3,700 new anchors from scratch. Of roughly 120 tested, seven matched or outperformed the strongest naturally occurring versions, and the enhanced displays made target cells more susceptible to CAR T-cell killing. This research was published in Nature Biotechnology.
Blocking cancer’s escape route
Joseph A. Fraietta, PhD (University of Pennsylvania) led an effort to leverage γδ T cells to address one way cancer escapes the grasp of T-cell therapies. Conventional T cells recognize cancer cells by the markers they display on their surface, presented in the context of what’s known as an HLA molecule. But if a cancer cell stops making a specific HLA molecule, then it can become invisible to T cells that recognize the associated markers. To overcome this, the team—which included Fraietta’s UPenn colleagues Carl H. June, MD, Bruce L. Levine, PhD, Daniel J. Powell, PhD, and Robert H. Vonderheide, MD, DPhil, as well as Michael T. Lotze, MD (University of Pittsburgh)—inserted a receptor targeting mutant KRAS into γδ T cells. Unlike conventional T cells, γδ T cells carry their own receptor that senses distress signals on cancer cells without relying on HLA, so the engineered cells could pursue their target two ways at once. The researchers also added an mRNA nanoparticle that prompts the body to make a molecule that can redirect T cells to a second cancer marker, in case of HLA loss. In mice with tumors missing the HLA molecule, the engineered cells alone gave only brief control, but adding the nanoparticle focused the immune response on the secondary target, clearing the tumors and extending survival. This research was published in the Journal of Hematology & Oncology.
A decade on, CAR T cells still on patrol
UPenn colleagues Carl H. June, MD, Joseph A. Fraietta, PhD, and Bruce L. Levine, PhD, were part of a team that tracked CD19-targeting CAR T cells in 38 patients with non-Hodgkin lymphoma for up to a decade after infusion. Among long-term responders with samples available beyond five years after treatment, most still carried detectable CAR T cells, and three showed the sustained absence of normal B cells that signals continued activity. In one patient who has been progression-free for a decade, CAR T cells made up 1.2% of their circulating T cells. Those long-lived cells had shifted to an unusual state—expressing neither CD4 nor CD8—and traced back to a single clone that had been vanishingly rare two weeks after infusion. This research was published in Nature Medicine.
When tumor T cells aim at the wrong target
Juan Fueyo, MD (The University of Texas MD Anderson Cancer Center) and colleagues proposed an explanation for a longstanding paradox: tumors are often full of immune cells that do not attack them. Between 20 and 80 percent of tumor-infiltrating lymphocytes are “bystanders” recognizing something other than cancer. Because tumors harbor bacteria and viruses, the authors argue many of those cells arrived in response to microbes rather than malignancy, diluting the anti-tumor response. Oncolytic virus therapy illustrates the problem: it draws T cells into tumors, but they mostly target viral antigens, producing a “pseudo-hot” tumor where infiltration and progression proceed simultaneously. Two implications are to select the T cells that actually recognize cancer before infusing them and to design oncolytic viruses that draw less attention to themselves. This hypothesis article was published in the Journal for ImmunoTherapy of Cancer.
Obstacles between glioblastoma and better outcomes
Antonio Chiocca, MD, PhD (Brigham and Women’s Hospital) and colleagues analyzed why glioblastoma survival has barely improved despite advances in molecular diagnostics and supportive care. Their assessment centers on three entrenched obstacles: tumors that differ genetically from one region to the next; a microenvironment that suppresses immune attack; and a blood-brain barrier that keeps most drugs out. Against those constraints, they weigh the potential benefits of strategies now being explored, including delivering therapies directly into the brain, biomarker-guided patient selection, and adaptable trial designs that can reflect the latest insights from the data. This review was published in Science Translational Medicine.
- Stephan A. Grupp, MD, PhD (Children’s Hospital of Philadelphia, CHOP) was featured in cell and gene therapy coverage throughout the summer. CBS News Philadelphia revisited the story of Emily Whitehead, the first child treated with CAR T-cell therapy under Grupp’s care and now more than a decade cancer-free. Additionally, CHOP announced that Grupp was co-senior author on a New England Journal of Medicine study supporting FDA expansion of exagamglogene autotemcel—a cell therapy created using CRISPR editing—to children as young as two with sickle cell disease or transfusion-dependent beta thalassemia. Lastly, Cancer Network covered the five-year results Grupp led from the ELIANA trial, published in the Journal of Clinical Oncology. Among 79 pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia, 88.6% reached complete remission, with an estimated five-year relapse-free survival of 47.3%.
- Carl H. June, MD (UPenn) spoke with Medscape about the expansion of CAR T-cell therapy beyond cancer into autoimmune disease, an application in which B-cell-targeting CAR T cells are being tested as a way to reset a misdirected immune system rather than suppress it long-term. Read the full interview at Medscape.
- Alexander Marson, MD, PhD (Gladstone-UCSF Institute of Genomic Immunology) was part of a team that built the first genome-wide CRISPR screen of human T cells inside living tumors and used it to identify two gene edits—knocking out P2RY8 and GNAS—that let CAR T cells infiltrate solid tumors in greater numbers and keep fighting once inside. Gladstone Institutes highlighted the work, which was published in Nature, in a news release, where Marson said the platform “fundamentally expands what’s possible” for developing next-generation cell therapies
- Katy Rezvani, MD, PhD (The University of Texas MD Anderson Cancer Center) led work explaining why CAR natural killer (NK) cell therapies made from donor cells perform inconsistently — and how to fix it. Her team identified a small subset of immature NK cells in donor material that are poor killers themselves and, worse, strip target antigen off tumor cells and accumulate it on their own surface. That stockpile acts as a decoy within the product, pulling the healthy CAR NK cells away from actual tumors and toward each other, driving them into a cycle of overactivation, metabolic stress, and exhaustion. Removing the offending subset before manufacturing restored the product’s potency and improved tumor control and survival in preclinical models of lymphoma and ovarian cancer. This research was published in Cancer Cell and covered by The ASCO Post.
- Renier Brentjens, MD, PhD (Roswell Park Comprehensive Cancer Center) and colleagues reported a 78% response rate in a phase 1 trial of patients with heavily pretreated relapsed/refractory multiple myeloma treated with both BCMA- and GPRC5D-targeting CAR T cells. Additionally, Dr. Brentjens and colleagues discussed the current understanding of interleukin-18 biology, as well as early results and challenges associated with IL-18-targeting therapies in the clinic. These articles were published in Blood and Nature Reviews Immunology.
- Christine E. Brown, PhD (City of Hope) and colleagues incorporated meditope technology into a programmable CAR T-cell system. By building “plug-and-play” CAR T cells with a docking socket, researchers can track, expand, or redirect a single-cell product to new tumor targets by adding the right molecule after infusion. This research was published in Cancer Immunology Research.
- Joseph A. Fraietta, PhD (UPenn) and colleagues found that a spectrum of delayed immune-related toxicities after BCMA CAR T-cell therapy for multiple myeloma is driven by CD4+ CAR T cells infiltrating those tissues and identified early inflammatory signatures that may allow the toxicities to be anticipated. This research was published in Molecular Therapy Oncology.
- Brent Hanks, MD, PhD (Duke University) and colleagues found that tumors that amplify the NLRP3 gene resist checkpoint inhibitor immunotherapy by suppressing MHC class 1 expression and hiding themselves from T cells—and showed that blocking NLRP3 restores that visibility and overcomes anti-PD-1 resistance in a gastric cancer model. This research was published in the Journal of Clinical Investigation.
- Marcela V. Maus, MD, PhD (Mass General Brigham Cancer Institute) and colleagues found that patients’ inherited genetic variation, including variants in the STXBP2 gene, influences the likelihood that CAR T-cell therapy benefits patients or causes serious toxicity. This research was published in Science Immunology.
- Shari Pilon-Thomas, PhD (H. Lee Moffitt Cancer Center & Research Institute) and colleagues profiled tumor-infiltrating lymphocyte (TIL) infusion products and their associated metastatic melanoma tumors from patients, identifying features that separate responders from non-responders while finding that prior checkpoint inhibitor treatment left TIL populations less fit. This research was published in Med.
- Matthias T. Stephan, MD (Fred Hutchinson Cancer Center) and colleagues developed a gel-like microfoam that can be injected under the skin and generate CAR T cells in the blood within hours, demonstrating that the newly programmed cells can disperse throughout the body and shrink distant tumors in mouse models of lymphoma and liver cancer. This research was published in Molecular Therapy.
- Merck and Moderna announced a phase 3 INTerpath-001 trial of Intismeran Autogene plus KEYTRUDA® with endpoints of recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with completely resected Stage IIB-IV Melanoma.
- Scientists at Hopp Children’s Cancer Center Heidelberg, Germany, report a remarkable response to a personalized T-cell therapy in a teenager with a metastatic, treatment-resistant kidney tumor. Results published in the New England Journal of Medicine show no evidence of active disease one year after treatment, highlighting the potential of the PRAME-specific T-cell therapy in an upcoming clinical trial.
- Vusolimogene oderparepvec-wtpg, an engineered oncolytic virus previously called RP1, received accelerated approval from the FDA for the treatment (in combination with the anti-PD-1 immunotherapy nivolumab) of patients with advanced cutaneous melanoma that has progressed after prior PD-1 therapy.
- Phase 3 clinical trial results from CG Oncology published in The Lancet Oncology showed that cretostimogene grenadenorepvec, an oncolytic immunotherapy delivered directly into the bladder, produced a complete response in 75% of patients with high-risk, BCG-unresponsive non-muscle-invasive bladder cancer, a population with few effective bladder-sparing options. Among the 112 patients treated in the single-arm BOND-003 Cohort C trial, side effects were largely mild and urinary, with no grade 3 or 4 treatment-related adverse events and no treatment-related discontinuations or deaths.
- First-in-human results for an armored GPC3-targeting CAR T-cell therapy in advanced liver cancer were published in Nature by AstraZeneca and partner AbelZeta. Among 36 heavily pretreated patients, tumors shrank in 32, with an objective response rate of 44.4% and median overall survival of 14.2 months; the cells are engineered with a decoy TGF-β receptor designed to blunt the immunosuppressive tumor microenvironment.
- Allogene Therapeutics received Regenerative Medicine Advanced Therapy (RMAT) and Fast Track designations from the FDA for cemacabtagene ansegedleucel (cema-cel), an off-the-shelf allogeneic CAR T-cell therapy, as first-line consolidation for patients with large B-cell lymphoma who test positive for minimal residual disease after initial treatment. In the interim analysis from the pivotal ALPHA3 trial, 58.3% of cema-cel patients cleared all signs of disease by day 45 compared with 16.7% under observation, with no cases of cytokine release syndrome or neurotoxicity and no hospitalizations for treatment-related adverse events.
- China’s IASO Biotechnology completed its acquisition of MediSix Therapeutics and its PEBL platform, which blocks target proteins from appearing on CAR T cell surfaces to prevent the cells from killing each other, a persistent obstacle to treating T-cell malignancies.
- Repligen agreed to acquire BioLife Solutions, adding CryoStor—the cryopreservation media used to protect cell therapies during storage and transport — to its portfolio. Many CAR T-cell therapies, including approved treatments, rely on BioLife products.
