Since the conventional cornerstones of cancer treatment (surgery, chemotherapy, and radiation therapy) manifest more and more limitations against multiple human malignancies, the novel immunotherapy is growing excitement with stutter steps, especially the CAR-T therapy. Hailed as “a living drug”, CAR-T is an excellent example of the application of basic research to the clinic.
Figure 1 The first fusion receptors (Creative Biolabs)
In detail, CAR stands for chimeric antigen receptor or artificial T cell receptor, which is engineered elaborately and endowing an immune effector cell (T cell) with an arbitrary specificity via a monoclonal antibody. The original CAR-T or the first-generation CAR consists of the intracellular domain from the CD3 ζ- chain and the primary transmitter of signals from endogenous TCRs, which showed success in pre-clinical trials and entered Phase I clinical trials in ovarian cancer, neuroblastoma and various types of leukemia and lymphoma. Although the anti-tumor activity was limited due to insufficient activation, persistence and homing to the cancer tissue, some significant effects indeed existed in patients with B-cell lymphoma treated with α-CD20-CD3 ζ CAR-modified T cells and some neuroblastoma treated with ScFv-CD3 ζ CAR-Ts. This is the most common form of CARs to fuse single-chain variable fragments (scFv) derived from monoclonal antibodies to CD3 ζ transmembrane and endo domain.
To augment the antitumor efficacy of 1st-generation CARs, the 2nd-generation CARs were designed to combine the intracellular signaling domains from various costimulatory protein receptors (e.g., CD28, 41BB, ICOS) incorporated in the cytoplasmic tail of the CAR to enhance the signaling. For instance, the CD19-targeted CARs incorporated with CD28 or 4-1BB signaling domains manifested remarkable complete remission rates in patients with refractory B-cell malignancies. Subsequently, the CD28-based CARs showed a brisk proliferative response and boost effector functions. Meanwhile, the 4-1BB-based CARs manifested a more progressive T cell accumulation.
Figure 2 The three generations of CARs (Creative Biolabs)
As the expectation of more antitumor efficacy, the 3rd-generation of CARs combined multiple signaling domains (e.g., CD3 ζ-CD28-41BB, CD3 ζ-CD28-OX40) to acquire further enhanced activation signals, proliferation, production of cytokines and effective function. For instance, the α-CD19-CD3 ζ-4-1BB CAR-Ts for chronic lymphocyte leukemia showed complete remission to infiltrate and lyse cancer tissue. Even better, a fraction of CAR-Ts functioned as a memory phenotype for preventing tumor relapses. Despite the significant therapeutic effect, the emerging uncontrollable activity accompanied with more antitumor efficacy caused life-threatening lysis activity as the most critical adverse effect or toxicity including clinically significant release of pro-inflammatory cytokines, pulmonary toxicity, multi-organ failure, and eventual death.
Figure 3 The 4th generation CAR (Creative Biolabs)
The previous CAR strategies are highly specific and useful in redirecting T cells targeting malicious cancer cells. However, the major limitation on solid tumors with a tremendous phenotypic heterogeneity and relapse due to antigen-negative cancer cells is the huge challenge to trigger a novel CAR strategy. The 4th-generation CAR-T is designed to shape the tumor environment by the inducible release of transgenic immune modifiers, such as IL-12, which augments T-cell activation, attracts and activates innate immune cells to eliminate antigen-negative cancer cells in the targeted lesion.
Figure 4 Representative CARs (Creative Biolabs)
Despite the classical route of CARs, more and more special CARs are designed and undergo intensive research such as TanCAR, physiological CAR (receptor/ligand-based), universal CAR (biotin/avidin-based), VHH-based CAR, etc.
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Aiming at clearing the tumor without the toxicity of conventional treatments, Creative Biolabs inherits advantages of CAR-T strategy to help researchers make scientific history fighting malicious cancers.
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