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Gene & Protein in Disease Genetically engineered T cells in cancer immunotherapy

hypoergia in solid tumors. Optimization of CAR structures types of B cell lymphoma and chronic B cell lymphocytic
to reduce side effects and improve their efficacy in solid leukemia, and several autologous CAR-T cell products
tumors has been widely studied to solve these problems. targeting CD19 have been approved, providing novel
therapeutic strategies for R/R B cell malignant diseases .
[14]
Another gene-engineered T cell therapeutic pattern
is T cell receptor-engineered T (TCR-T) cell therapy, Meanwhile, the products of CAR-T cells targeting
BCMA have been approved by the U.S. Food and Drug
which exhibits unique advantages in the treatment of Administration (FDA) in the treatment of R/R multiple
solid tumors . TCR-T cells evoke a cytotoxic response [3]
[4]
and induce tumor regression in vivo . To date, only one myeloma . However, plenty of clinical trials have been
[5]
conducted on second-generation CAR-T cells in the
TCR-T cell product (Kimmtrak) has been approved for the treatment of solid tumors without any breakthroughs .
[15]
treatment of unresectable or metastatic uveal melanoma . Scientists have extensively explored solutions to the
[6]
More clinical trials of tumor-specific/associated current issues with second-generation CAR-T cells, such as
antigen- or neoantigen- modified TCR-T cells in solid reducing toxicity by altering CAR structure or expressing
tumors are underway . While various challenges exist in a “suicide gene” , and improving the therapeutic effect
[7]
[16]
the application of adoptive T cell therapy, basic research with dual-target CAR-T cells [17,18] . Expression of two
and clinical trials have been conducted to mitigate these costimulatory molecules enhances the amplification
limitations. As the technology develops, the accumulation capacity and anti-tumor effect of CAR-T cells, which are
of clinical trial data will support the approval of more regarded as third-generation CAR-T cells . Chemokine
[15]
engineered T cell products and benefit more patients with receptors, cytokines, or transcription factor-modified
tumors. In this review, we discuss the current, challenges, CAR-T cells are named fourth-generation CAR-T cells .
[19]
and recent advances in the use of gene-engineered T-cells Meanwhile, dual- or three-target modified CAR-T cells for
in cancer immunotherapy. Furthermore, we highlight preventing antigen escape, or other gene-editing strategies
potential strategies to conquer the disadvantages of for improving the efficacy are defined as next-generation
extending adoptive T cell therapy. CAR-T cells. The clinical application and basic study of
2. The concept and generation of CAR-T cell CAR-T cell therapy in hematological malignancies and
solid tumors are described in detail below.
therapy
CAR-T cells are prepared using gene-editing technology 3. CAR-T cell therapy in hematological
(i.e. viral or non-viral vector transfection) to endow malignancies
common T cells with a single-chain variable fragment Many clinical trials of differentially targeted CAR-T cells
(ScFv) containing recognized tumor antigens and signals in various hematological malignancies are currently
of T cell activation, producing specific recognition, underway, including CD19, CD20, CD7, CD30, CD38,
and cytotoxic functions independent of major BCMA, CD22, CD70, CD79b, and dual targets. It was
[8]
histocompatibility complex expression . Specifically, reported that 80 – 94% of R/R B-ALL patients who
CAR-T cells rely on ScFv in the CAR structure, which received CD19-targeted CAR-T cell infusion achieved
recognizes tumor antigens and promotes T cell activation complete remission (CR) . Moreover, 80% of diffuse
[20]
and expansion . Activated CAR-T cells secrete cytokines, B-cell lymphoma patients had an objective response, and
[9]
such as interleukin (IL)-2 and interferon (IFN)-, which nearly 40% had a long progression-free survival . The
[21]
can induce apoptosis of target cells. In 1987, Kuwana et al. result of ZUMA-2, a large clinical trial of CD19 CAR-T cell
developed the first CAR prototype by fusing the V region product TECARTUS, showed that 67% of patients with
of immunoglobulin with the constant region of the TCR . R/R mantle cell lymphoma achieved a CR . ZUMA-5
[10]
[22]
The first-generation CAR construct contained the ScFv indicated that R/R indolent non-Hodgkin’s lymphomatous
and CD3 signaling regions, which endowed T cells with (NHL) patients receiving axicabtagene ciloleucel therapy
transient activation and cytotoxicity, but insufficient anti- had a high overall response (92%) and CR (74%) . More
[14]
tumor efficacy . In subsequent studies and clinical trials, clinical trials have been conducted to evaluate the potential
[11]
second-generation CAR-T cells were developed, which of CD19 CAR-T cells as a first- or second-line therapeutic
integrated costimulatory signaling molecules CD28 or method for large B-cell lymphoma [1,2] . When 41 R/R
CD137 into the intracellular signaling domain improving Hodgkin’s lymphoma patients received a CD30 CAR-T
the cytotoxicity and existence of CAR-T cells [12,13] . With cell infusion, the total OR and CR rates were 72% and
second-generation CAR-T cells targeting CD19 produces a 59%, respectively . CAR-T cells (idecabtagene vicleucel)
[23]
high objective response rate (ORR) in relapsed/refractory targeting BCMA have a high response rate in R/R multiple
(R/R) acute B cell lymphocytic leukemia (B-ALL), specific myeloma and have been approved by the U.S. FDA. In a

Volume 1 Issue 1 (2022) 2 https://doi.org/10.36922/gpd.v1i1.114