Next-generation Cellular Immunotherapy: Reprogramming Immune Cells Inside the Body

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Topic Description

Post Date: September 2, 2026

Expiration Date: September 2, 2028

Purpose

The overarching purpose of this topic is to encourage basic, preclinical research and early clinical testing of in vivo immune cell engineering approaches to reprogram immune cells within the body, including but not limited to T cells, Natural Killer (NK) cells and macrophages, for treating various diseases including cancer, autoimmune, infectious and age-related diseases, and for use in regenerative medicine. The in vivo immune cell engineering may involve the use of viral vectors (such as lentiviral or adeno-associated viral vectors) or non-viral nanocarriers (such as lipid nanoparticles or LNPs) for delivery of genetic material (such as DNA or mRNA). The genetic material could encode chimeric antigen receptors (CARs), T cell receptors (TCRs) or other functional elements, and/or gene editing machinery for reprogramming immune cells in situ. The proposed research may include development and testing of novel technologies and methodologies for increasing specificity and efficiency of immune cell targeting and transduction in vivo, or may aim to improve biodistribution and safety or enhance efficacy and persistence of engineered immune cells in preclinical models and in early clinical studies. In summary, this topic promotes innovative research that advances in vivo immune cell engineering-based cell therapy for cancer and other diseases, ensuring its benefits to be broadly accessible and effectively integrated into future healthcare.

Background

Adoptive cellular therapies (ACTs) such as CAR-T cells have transformed the treatment of hematologic malignancies but challenges remain for treatment of solid tumors because of poor immune cell trafficking, limited persistence, and immunosuppressive tumor microenvironments (TMEs). Nonetheless, ACT development for solid tumors is rapidly expanding, encompassing autologous and allogeneic engineered T, NK and other immune cells. Beyond oncology, cellular therapies are being explored for autoimmune, infectious and age-related diseases, and regenerative medicine. Despite their promise, current ACT approaches face substantial practical barriers, including lymphodepletion, leukapheresis, ex vivo cell modification and expansion, GMP manufacturing, specialized facilities, and weeks-long processing times. Such complexity makes ACTs slow, costly, and inaccessible to many patients. In contrast, the in vivo engineering of immune cells approach has emerged as a transformative alternative to enable immune cells to be engineered inside the body using in vivo gene delivery technologies, bypassing the tedious, costly and time-consuming process of current ACTs, offering true off-the-shelf in vivo cellular immunotherapies. In short, this approach removes a major logistical bottleneck and enables treatment for rapidly progressing diseases where patients can often not afford the long wait.

Participating ICOs

National Cancer Institute (NCI)

NCI encourages research and development of in vivo immune cell engineering-based methods for testing in preclinical models and early clinical trials for hematologic and solid tumors. Topics may include, but are not limited to:

  • Viral vector-based delivery of DNA fragments carrying tumor-specific CARs, TCRs, costimulatory domains and/or other functional elements
  • Nonviral-based delivery using LNPs or other synthetic nanocarriers for mRNA, siRNA and other cargos
  • Novel delivery methods such as LNPs, nanocarriers, biodegradable nanomaterials or other delivery vehicles to introduce genetic materials for arming or reprogramming immune cells
  • Novel gene editing methods, such as CRISPR/Cas9, base or prime editing, delivered with nanovehicles for genetic editing or epigenetic reprogramming of immune cells 
  • Preclinical toxicity and safety studies and pilot clinical trials informed by biomarkers 
  • Combined use with other therapies, such as immune checkpoint blockade or TME-modulating agents
ICO Scientific Contact:
Zhang-Zhi Hu, M.D.
[email protected]

National Institute of Allergy and Infectious Diseases (NIAID)

NIAID encourages basic, translational, and early clinical research to develop engineered cellular therapies for infectious, autoimmune, and other immune-mediated diseases, including targeted modulation of protective or pathogenic immune responses that induce durable disease control while preserving protective immunity. Strategies of interest include the improvement of:

  • Tissue, antigen, and cell specificity for enhancing protective immunity or eliminating/reprogramming pathogenic immune subsets, including autoreactive innate and adaptive immune cells.
  • Scalability, cost reduction, and expansion of access to off-the-shelf or in vivo delivery approaches that minimize preconditioning.
  • Safety, including mitigation of off-target effects, unintended tissue injury, prolonged immune dysregulation, oncogenic risk, and improved control and reversibility of therapeutic activity.
ICO Scientific Contact:
Jeffrey Rice, Ph.D.
[email protected]

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

In the context of this topic, NIAMS encourages basic, translational, and clinical research that advances in vivo immune cell engineering-based cell therapy diseases, including rheumatic, autoimmune, autoinflammatory, and musculoskeletal and bone diseases and conditions. 

ICO Scientific Contact:
Marie Mancini, Ph.D.
[email protected]

National Institute of Biomedical Imaging and Bioengineering (NIBIB)

NIBIB is interested in developing technologies to engineer immune cells in vivo for a variety of diseases. Potential topics include:

  • New types of engineered viruses, artificial cells for delivery of genetic material
  • Novel delivery methods such as using lipid nanoparticles, nanocarriers, biodegradable nanomaterials or other delivery vehicles to introduce genetic materials for arming or reprogramming of immune cells
  • Novel gene editing methods, synthetic receptors and transmembrane chimeric antigen receptors 
  • Nucleases and genome editors for DNA manipulation and regulation
  • Synthetic genetic circuits for engineering T-cells, natural killer cells, macrophages for immune regulation and cancer therapy
  • Biomaterials for enhancing immunotherapy
  • Development of novel platforms to engineer immune cells in vivo using microphysiological systems to model and evaluate targeting, transduction efficiency, and/or therapeutic function
ICO Scientific Contact:
Tuba Fehr, PhD
[email protected]

National Institute of Dental and Craniofacial Research (NIDCR)

NIDCR seeks to support research and the advancement of technologies to treat dental, oral, and craniofacial diseases and conditions. 

  • Novel viral vector–based delivery platforms, and nonviral delivery approaches employing lipid nanoparticles and other synthetic nanocarriers, for the efficient and targeted delivery of nucleic acids or protein cargos.
  • Innovative gene-editing technologies, including CRISPR/Cas9 and base or prime editing, to enable precise and durable genetic and epigenetic modification of immune cells in vivo.
  • Combination strategies that integrate immune engineering approaches with established therapeutic modalities, including immune checkpoint blockade, autoantigen- and antibody-based therapies, and cytokine- and chemokine-mediated modulation.
  • Advanced data science, artificial intelligence/machine learning, and computational modeling approaches to elucidate mechanisms of action and optimize the design and performance of immune engineering approaches and cellular therapies.
IC may give special consideration to support meritorious applications in this topic area.
ICO Scientific Contact:
Zhong Chen, MD, PhD
[email protected]

Office of Research on Women's Health (ORWH)

The Office of Autoimmune Disease Research in the Office of Research on Women’s Health (OADR-ORWH) is interested in supporting research and development of in vivo immune cell engineering-based methods, including:

  • Design and engineering of next‑generation cellular therapies, including CAR‑T and CAAR-T cells, regulatory T‑cells (Tregs), NK cells, engineered CARs and TCRs, costimulatory domains, and other immunocytes and functional elements.
  • Development of data science and computational approaches to interrogate the mechanisms of novel cellular therapies, including analysis of new or existing early‑phase and pooled clinical trial data to define immunologic treatment windows and identify predictors of therapeutic response.
  • Advancement of translational research to enable and accelerate clinical trials of cellular therapies for autoimmune diseases.

The engagement of people living with or at risk for autoimmunity is strongly encouraged to ensure research has direct relevance to human health.

This office does not award grants. Applications must be relevant to the objectives of at least one of the participating Institutes or Centers listed in this topic.
ICO Scientific Contact:
Victoria Shanmugam, MBBS, FRCP, FACR, CCD
[email protected]

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