In Vivo CAR-T Companies: A Deep Dive Into Current Advances

CAR-T cell therapy has transformed cancer treatment, offering a personalized immune-based approach with remarkable success in certain blood cancers. Traditional CAR-T therapies require modifying a patient’s T cells outside the body before reinfusion, but in vivo CAR-T aims to engineer T cells directly within the patient. This could reduce costs, shorten treatment timelines, and improve accessibility.

Advances in gene delivery, synthetic biology, and immunotherapy have accelerated progress. Researchers are refining targeting mechanisms, enhancing safety, and expanding applications beyond oncology.

Major In Vivo CAR T Organizations

Several biotechnology and pharmaceutical companies are leading the development of in vivo CAR-T therapies, each employing distinct strategies to optimize gene delivery, enhance efficacy, and ensure safety.

Moderna has leveraged its mRNA platform to encode CAR constructs directly within the body, bypassing the complexities of ex vivo cell manipulation. Their approach builds on mRNA vaccine success, using lipid nanoparticles (LNPs) to deliver genetic instructions that reprogram T cells in situ. Preclinical studies have shown robust CAR expression and tumor clearance, positioning Moderna as a frontrunner.

Poseida Therapeutics focuses on non-viral gene delivery, particularly its piggyBac transposon system, which enables stable CAR integration without risks associated with viral vectors. This technology has shown promise in preclinical models, offering a scalable alternative to traditional gene editing. Poseida’s in vivo CAR-T programs are advancing toward clinical evaluation, with early data suggesting durable responses and minimal off-target effects.

Capstan Therapeutics employs a nanoparticle-based approach to deliver CAR-encoding RNA directly to T cells. By refining lipid nanoparticle formulations to selectively target immune cells, Capstan aims to improve specificity and reduce systemic toxicity. Collaborations with leading academic institutions have accelerated their research.

Umoja Biopharma takes a different route, using synthetic inducers to activate CAR expression within the body. Their VivoVec platform employs a lentiviral vector system for in vivo administration, enabling controlled and sustained CAR-T activity. This method has demonstrated potential in preclinical studies, particularly in addressing T cell persistence and exhaustion.

Targeted Disease Categories

In vivo CAR-T therapies are being explored for cancers and immune-related disorders. By engineering T cells within the body, researchers aim to overcome limitations of traditional CAR-T, such as manufacturing delays and patient-specific variability.

Hematologic Malignancies

Blood cancers, including leukemias, lymphomas, and multiple myeloma, have been the most successful targets for CAR-T therapy. In vivo approaches seek to improve upon existing treatments by streamlining production and reducing costs.

Moderna’s mRNA-based CAR-T platform is being investigated for B-cell malignancies, using lipid nanoparticles to deliver CAR constructs directly to T cells. Preclinical models have shown promising tumor clearance.

Poseida Therapeutics is advancing in vivo CAR-T therapies for hematologic cancers using its piggyBac transposon system, which allows for stable gene integration without viral vectors. This method has demonstrated prolonged CAR-T persistence in animal models, potentially enhancing long-term remission rates.

Capstan Therapeutics is developing nanoparticle-based delivery systems targeting CD19-positive malignancies, aiming to improve specificity while minimizing systemic toxicity. These efforts reflect a growing interest in refining CAR-T therapies for blood cancers.

Solid Tumors

Unlike blood cancers, solid tumors present challenges due to the tumor microenvironment, antigen heterogeneity, and physical barriers to T cell infiltration. In vivo CAR-T strategies aim to enhance T cell expansion and persistence directly within the patient.

Umoja Biopharma’s VivoVec platform is being explored for solid tumors, using lentiviral vectors to induce CAR expression in situ. This approach has shown promise in preclinical studies, particularly in improving T cell infiltration.

Capstan Therapeutics is investigating lipid nanoparticle formulations designed to selectively transfect T cells with CAR constructs against solid tumor markers. Early studies suggest this method could enhance tumor targeting while reducing off-target effects. Researchers are also exploring combination strategies, such as pairing in vivo CAR-T with checkpoint inhibitors, to improve efficacy.

Autoimmune Conditions

Beyond oncology, in vivo CAR-T therapies are being investigated for autoimmune diseases, where dysregulated immune responses cause tissue damage. The goal is to reprogram T cells to selectively suppress pathogenic immune activity while preserving normal function.

Poseida Therapeutics is exploring in vivo CAR-T for autoimmune diseases using its non-viral gene delivery platform. By modifying T cells to eliminate autoreactive immune cells, this strategy could offer a durable treatment option with fewer side effects than traditional immunosuppressive therapies.

Researchers are also investigating in vivo CAR-T to induce regulatory T cells (Tregs), which could help restore immune balance in diseases such as rheumatoid arthritis. These efforts highlight the expanding scope of in vivo CAR-T beyond cancer treatment.

Notable Delivery Systems

The success of in vivo CAR-T therapies hinges on precise and efficient gene delivery systems that introduce CAR constructs into T cells while minimizing unintended effects.

Lipid nanoparticles (LNPs) have gained traction due to their ability to encapsulate and transport genetic material with high specificity. Originally developed for mRNA vaccines, these nanoparticles have been adapted for CAR-T applications by modifying their lipid composition to enhance uptake by T cells. Studies have demonstrated that optimized LNP formulations can achieve robust CAR expression in vivo, with preclinical models showing effective tumor clearance.

Beyond lipid-based carriers, non-viral gene delivery systems such as DNA transposons offer a compelling alternative by enabling stable genetic integration without the risks of viral vectors. The piggyBac transposon system, for example, has been explored for in vivo CAR-T due to its ability to insert large genetic payloads into T cells with sustained expression. This approach has shown long-term CAR-T persistence in preclinical models without significant genomic instability. Compared to viral vectors, transposon-based methods may reduce manufacturing complexity and improve scalability.

Lentiviral and adeno-associated viral (AAV) vectors, despite their established role in gene therapy, are being refined for safer and more efficient in vivo CAR-T delivery. Advances in vector engineering have led to tissue-specific promoters and targeting ligands that enhance selectivity for T cells while minimizing off-target transduction. Researchers are also exploring self-inactivating viral constructs to reduce the risk of insertional mutagenesis. Early studies suggest these modifications could improve the safety profile of viral-based in vivo CAR-T therapies while maintaining high transduction efficiency.

Collaborative Research Programs

The development of in vivo CAR-T therapies has been accelerated by strategic collaborations between biotechnology companies, academic institutions, and government agencies. These partnerships integrate expertise from multiple disciplines, including synthetic biology, nanomedicine, and gene editing, to address technical challenges and streamline the transition from preclinical models to clinical application.

A key collaboration is between the University of Pennsylvania and Capstan Therapeutics, focused on enhancing lipid nanoparticle-based gene delivery. Leveraging Penn’s research in mRNA and nanoparticle technology, Capstan has developed formulations that selectively target T cells while minimizing systemic exposure. Preclinical data show precise CAR expression with minimal toxicity, laying the foundation for clinical trials.

Poseida Therapeutics has partnered with the National Cancer Institute (NCI) to explore non-viral gene delivery techniques, particularly the piggyBac transposon system, which has shown potential for durable CAR-T expression without the risks associated with viral vectors.

Clinical Trials Underway

Multiple clinical trials are assessing the safety, efficacy, and scalability of in vivo CAR-T therapies. These trials aim to validate preclinical findings, optimize dosing strategies, and evaluate long-term patient outcomes.

Early-stage studies are primarily focused on hematologic malignancies, where CAR-T therapies have demonstrated success in ex vivo applications. Companies like Capstan Therapeutics and Moderna have initiated trials targeting B-cell malignancies using lipid nanoparticle-based gene delivery. Preliminary results suggest in vivo CAR-T administration can achieve comparable tumor regression to conventional CAR-T therapies while reducing logistical challenges.

In addition to oncology, clinical trials are exploring autoimmune applications. Poseida Therapeutics is conducting early-phase studies on in vivo CAR-T therapies for conditions such as systemic lupus erythematosus, aiming to selectively eliminate autoreactive immune cells. These trials will provide critical insights into the durability of in vivo CAR-T responses and potential off-target effects.

Regulatory agencies such as the FDA are monitoring these developments to ensure safety while facilitating expedited pathways for promising candidates. As more data emerge, these trials will shape the future of in vivo CAR-T therapy and its feasibility for widespread clinical use.