Research and development leading to the discovery of novel antibiotics has waned in recent years. At the same time, the emergence and spread of antimicrobial resistance has compounded the global danger to human health from bacterial infections.
Many known chemotherapeutic drugs kill abnormal cells through a process called apoptosis. Bcl-2 proteins are negative regulators of apoptosis that control cell survival and death. Increased expression of anti-apoptotic Bcl-2 proteins commonly occurs in up to 30% of all cancers, providing cancer cells a pro-survival advantage to evade cell death, grow, and proliferate. Drugs targeting these specific anti-apoptotic proteins are potential anti-cancer therapeutics.
Targeting the CD22 receptor of B-cells with chimeric antigen receptor (CAR)-T cells has been a promising new therapy to treat B-cell malignancies in clinical trials, inducing remission in 70% of patients with relapsed acute lymphoblastic leukemia (ALL). However, diminished CD22 expression on B-cell surface can lead to relapse and decreased remission duration, which may be prevented through increasing CAR-T affinity towards CD22.
Treatment of B-cell acute lymphoblastic leukemia (ALL) and lymphoma using chimeric antigen receptors (CARs) targeting B-cell surface protein CD19 has demonstrated impressive clinical results in children and young adults. Despite the promising results from CD19 CAR therapy, up to 40% of patients, who initially achieve remission, eventually relapse. Relapse or non-response to CD19-directed CAR therapy may be due to low or diminished CD19 expression. Such patients would be predicted to benefit from CAR therapies targeting other B-cell surface proteins, such as CD22.
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.
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.