This month’s ACGT Research News Roundup covers ongoing pharma M&A activity for in-vivo CARs, an inhalable gene therapy receiving RMAT designation, the launch of the first head-to-head study for CAR T therapies, and features research from our ACGT Scientific Advisory Council (SAC) and Research Fellows. 

Orna’s in vivo CAR-T pipeline includes potential best-in-class programs to reset the immune system and address B-cell-driven autoimmune diseases. Acquisition provides a broad platform for long-term innovation in genetic medicine and in vivo cell engineering. 

PiNACLE – H2H is a Phase 3 head-to-head CAR T-cell randomized controlled clinical trial of ronde-cel versus Investigator’s choice of either liso-cel or axi-cel in patients with R/R LBCL receiving treatment in the 2L setting. Patients randomized to ronde-cel will be treated with a dose of 100 x 106 CAR T cells; patients in the control arm will be treated as per the product label.

U.S. IND represents the second regulatory clearance for KLN-1010 and enables the first multi-center clinical trial in the U.S. for an anti-BCMA in vivo CAR-T program. 

Siren Biotechnology, pioneers of Universal AAV Immuno-Gene Therapy for cancer, today announced that the U.S. Food and Drug Administration (FDA) has cleared the Company’s first Investigational New Drug (IND) application, enabling the initiation of its first-in-human clinical trial. With this clearance, Siren officially advances to a clinical-stage biotechnology company. The IND clearance supports the evaluation of Siren’s lead investigational program in adult patients with recurrent high-grade glioma and represents a significant regulatory milestone for the Company. Siren believes this marks the first FDA-cleared IND for an adeno-associated virus (AAV)-based therapy in an oncology indication, underscoring the growing potential of gene therapy approaches in cancer. 

Data to support the FDA’s RMAT designation included early clinical evidence from the Company’s ongoing KYANITE-1 study that demonstrated consistent and meaningful antitumor activity, including durable responses and clinically significant tumor reductions, in patients with heavily pre-treated advanced NSCLC receiving inhaled KB707.

The BBVA Foundation Frontiers of Knowledge Award in Biology and Biomedicine has gone in this eighteenth edition to Carl June (University of Pennsylvania) and Michel Sadelain (Columbia University) for revolutionizing the treatment of cancer by means of CAR-T cell immunotherapy. The two laureates pioneered this innovative therapeutic strategy in which T cells are extracted from the patient’s own immune system, grown in the lab, and genetically engineered to recognize and selectively destroy cancer cells when infused back into the body, leading to disease remission. 

A team led by investigators at Dana-Farber Cancer Institute and Mass General Brigham has shown that a single injection of an oncolytic virus—a genetically modified virus that selectively infects and destroys cancer cells—can recruit immune cells to penetrate and persist deep within brain tumors. The research, published in Cell, details how this therapy prolonged survival in patients with glioblastoma, the most common and malignant primary brain tumor, in a recent clinical trial. 

Small cell lung cancer (SCLC), a highly lethal disease, limits T cell responses by downregulating major histocompatibility (MHC) class I molecules. Because chimeric antigen receptor (CAR) T cells are not MHC restricted, they may provide a powerful strategy against SCLC. However, few CAR targets for SCLC are known. In this paper, the researchers show that B7-H3/CD276 is expressed in SCLC and thoracic SMARCA4-deficient undifferentiated tumors (UTs) that can clinicopathologically mimic SCLC. Thoracic SMARCA4-deficient UTs limit killing by B7-H3 CAR T cells via secretion of transforming growth factor β1 (TGF-β1). To overcome tumor-driven CAR T cell suppression, researchers knocked in c-JUN alongside a B7-H3 CAR into the TRAC locus of primary human T cells utilizing CRISPR-Cas9. Non-viral c-JUN+B7-H3 CAR T cells show enhanced killing of both SCLC cells with low antigen density and thoracic SMARCA4-deficient UTs, providing a platform to address these highly aggressive entities. They also provide evidence that good manufacturing practice (GMP) clinical-scale manufacturing is feasible for c-JUN+B7-H3 CAR T cells.

In this study, the researchers developed a mathematical model of CAR T-cell therapy for glioblastoma to explore combinatorial antigen targeting across multiple CAR T-cell treatments, accounting for the spatial heterogeneity of antigen expression. The hybrid model created using the multicellular modeling platform PhysiCell, couples partial differential equations that describe the tumor microenvironment with agent-based models for glioblastoma and CAR T-cells. 

Tumor-associated macrophages (TAMs), which commonly express FOLR2 or TREM2, are enriched in solid tumors and keep the tumor microenvironment (TME) immunosuppressed. In this study, the researchers introduce IL-12-expressing CAR-T cells targeting FOLR2 or TREM2 to deplete pro-tumor TAMs and reprogram the TME. Treatment with IL-12-armored anti-TAM CAR-T leads to significantly improved survival in metastatic ovarian and lung cancer models. 

Glioblastoma (GBM) evolves within a microenvironment abundant in oligodendrocyte-lineage (OL) cells. In this study, the researchers used single-cell and spatial transcriptomics from primary and recurrent GBM tumors, immunohistochemistry, cytokine profiling, and migration assays to show that GBM cells recruit OLs to the tumor border via fractalkine (CX3CL1/CX3CR1) signaling.

In this study, the researchers demonstrate that LRRC15-CAR T cells exhibit anti-osteosarcoma activity and maintain a favorable safety profile across multiple preclinical models. The results provide rationale to develop LRRC15-CAR T cell therapy for early-phase clinical testing in patients with osteosarcoma and potentially other LRRC15-positive malignancies.  

In vivo CAR therapies are rapidly emerging as a strategy to address the scalability, access, and toxicity limitations associated with conventional ex vivo CAR-T cell products. This article reviews viral and LNP–RNA platform technologies, emerging clinical evidence, and key safety and regulatory considerations relative to established CAR-T and immune cell engager approaches. While early progress is encouraging, careful translational evaluation is essential to determine whether in vivo CAR strategies can ultimately meet or surpass current standards of care across oncology, autoimmunity, and other indications. 

In a phase I study, researchers tested a pooled synthetic long peptide vaccine targeting the six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab in resected pancreatic adenocarcinoma. Co-primary endpoints include safety and maximal percent change of IFNγ-producing mutant KRAS T cell responses in the blood within 17 weeks.  

A team from the University of Geneva (UNIGE) and the Ludwig Institute for Cancer Research reveals how the ‘hijacking’ of neutrophils, a type of immune cell, promotes cancer growth and could provide insights into disease progression. The scientists found that neutrophils, a type of immune cell, undergo reprogramming when they interact with the tumor ecosystem and contribute to its progression. They then produce a molecule — the chemokine CCL3 — which promotes cancer growth rather than fighting it. 

Researchers in the UK systematically identified genetic determinants of cancer cell sensitivity to anti-tumor immunity by performing whole-genome CRISPR-Cas9 knockout screens in autologous tumoroid-T cell co-cultures, in isogenic cancer cell models deficient in interferon signaling, and across four cytokines.  

In a first-in-human study, researchers at The University of Texas MD Anderson Cancer Center observed strong responses and early signs of antitumor activity in patients with difficult-to-treat non-Hodgkin lymphomas who received the novel cell therapy RB-1355. Thirteen patients with advanced B-cell or T-cell lymphomas were treated as part of the trial. Two individuals with diffuse large B-cell lymphoma who had relapsed or had not responded to CAR T cell therapy achieved complete remissions. One patient remained disease-free more than 100 days after treatment. Partial responses were observed in patients with peripheral T-cell lymphoma and mycosis fungoides. These patients had no standard treatment options left.