Main Menu

T cell immunotherapy is used in the treatment of various pathologies – including cancers and infections. Current therapies employ chimeric antigen receptors (CARs) consisting of the intracellular fragment of CD3-zeta as the signaling domain with varied combinations of co-stimulatory, transmembrane, spacer/hinge, and extracellular targeting domains. While effective in treating hematological malignancies, CAR T cells need to be activated through T cell receptor (TCR) activation.

Adoptive cell transfer (ACT) and T-cell receptor (TCR) therapies use lymphocytes that target somatic mutations expressed by tumors cells to treat cancer patients. One of the challenges of these therapies is the identification and isolation of mutation-specific cells and TCRs. While neoantigen specific cells are relatively abundant in the tumor, they are far less common in peripheral blood, a more accessible source of T cells. 

The treatment of cancer using immunotherapies has garnered substantial attention and excitement considering the clinical benefits observed in patient populations previously refractory to treatment. Tumor infiltrating T cells can significantly impact cancer progression and immunotherapy response; however, immunosuppressive tumor microenvironments can impede antitumor T cell induction, trafficking, and local activity. Thus, personalized immunotherapy approaches have shown limited efficacy against most solid tumors.

Retinal Degenerations (RD) are the leading cause of blindness in the United States. The degeneration of the Retinal Pigment Epithelium (RPE) is associated with various types of RD such as Stargardt’s disease, retinitis pigmentosa, choroideremia, Late-Onset Retinal Degeneration (L-ORD), and Age-related Macular Degeneration (AMD). The RPE as a layer of cells in the back of the eye. Therefore, it is essential to maintain the health and integrity of retinal photoreceptors.

The chemokine receptor, CCR4 is a seven transmembrane G protein-coupled cell surface receptor molecule with selective expression on cells of the hematopoietic system. In adult T cell leukemia (ATL), the cell-surface expression of CCR4 on leukemic cells has been found to be nearly universal. Therefore, a CCR4-directed chimeric antigen receptor (CAR) -cell may provide an effective therapeutic against ATL.

Mesothelioma is an aggressive cancer covering anatomic surfaces (e.g. lining of the lungs, heart, abdomen, etc.) that resists multi-modality therapies. Regional recurrence of mesothelioma from residual tumor cells prevents long-term benefits after surgical resection. Furthermore, there is no clinical consensus on intracavitary adjuvants that are effective in extending the tumor reduction effect of surgery.

Hematopoietic and pluripotent stem cells can be differentiated into T cells with potential clinical utility. Current approaches for in vitro T cell production rely on Notch signaling and artificial mimicry of thymic selection. However, these approaches result in unconventional or phenotypically aberrant T cells; which may lead to unpredictable behavior in clinical use. Thus, there exists a need for improved methods of generating conventional T cells in vitro from stem cells.
 

RNA interference (RNAi) is a biological response to double-stranded RNA that regulates expression of protein-coding genes and is a natural mechanism for gene silencing. Delivery of short, interfering RNA (siRNA) leads to RNAi of the targeted genes. 

Peptides corresponding to transmembrane domains of a number of integral proteins were discovered to spontaneously self-assemble in aqueous solutions into stable and remarkably uniform nanoparticles.  Researchers at the NCI’s Cancer and Inflammation Program have developed fully synthetic, peptide-based, virus-like nanoparticles capable of delivering cytotoxic, radioactive, and imaging agents. 

Structure and function of tumor-target self-assembling particles:

Adoptive cell therapy (ACT) using tumor-specific T cells can produce positive clinical responses in some cancer patients. Nevertheless, several obstacles to the successful use of ACT for the treatment of cancer and other conditions remain. For example, one or more of the in vivo persistence, survival, and antitumor activity of tumor-specific T cells can, in some cases, decrease following adoptive transfer. Accordingly, there is a need for methods of obtaining a robust population of tumor-specific T cells for ACT.