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

Twenty-one patients with R/R B-ALL received U-CAR-T
cell infusion, and CR or non-hematologic CR was achieved
in 14 patients within 28 days. CRS occurred in 91% of these
patients, three patients had Grade 3 – 4 CRS, two patients
experienced Grade 1 skin rejection, and eight patients
manifested Grade 1 – 2 neurotoxicity. It has been reported
that CD19/CD22 dual-target U-CAR-T cells created by
CRISPR/Cas9-edited TRAC and CD52 produced a CR rate
of 83.3% without dose-limiting toxicity, graft-versus-host
disease, neurotoxicity, or other adverse events associated
with genome editing in six R/R B-ALL patients . Clinical
[69]
trials of allogeneic CAR-T cells in other malignancies are
in progress.
6. CAR-T cell therapy in solid tumors
CAR-T cell therapy was first intended for use in treating
solid tumors, but due to the specificity of the target, the
complexity of the tumor microenvironment and tumor
Figure 3. Reducing antigen immune escape with dual- or multiple- target heterogeneity, T cell recruitment, and other factors caused
CAR-T cells. Multiple CAR and tandem CAR structures are designed poor efficacy in solid tumors . With the development
[71]
to improve the ability of CAR-T cells to recognize different antigens on of efficient gene-editing technology, an endless stream of
tumor cell surface for preventing antigen immune escape.
CAR-T therapies has emerged. The selection of CAR-T
cell-targeted antigen has important effects on both
many limitations. First, due to their specific matching as therapeutic efficacy and safety. Unlike hematological
well as long production preparation and quality control tumors, the therapeutic targets in solid tumors are mostly
period, patients with rapid disease progression may over-expressed antigens. Thus, those tumor-associated
miss the treatment opportunity for CAR-T cell infusion. antigens (TAAs) with relatively specific expression and
Second, in infants, severe patients, and some patients with higher individual positivity rates may represent optimal
immune system damage, their own T cells cannot be used targets for CAR-T cell therapy. At present, the main
for CAR-T cell preparation or will undergo culture failure, targets of relevant clinical trials in solid tumors are GPC3,
and they will not be able to receive autologous CAR-T mesothelin, EGFR, PSPA, CEA, and GD2. Although the
cell infusions. Moreover, the consistency of individual development of CAR-T cell therapy is rapid, there are
products is difficult to guarantee and the production still many limitations and challenges in solid tumors.
cost is high, thereby limiting the large-scale production These major challenges include tumor heterogeneity and
of CAR-T cells and their wide application. Therefore, antigen escape, insufficient immune cell infiltration, tumor
exploring U-CAR-T cells has become a focus in the field immunosuppressive microenvironment, T cell exhaustion,
of immunotherapy [64,65] . TALEN and CRISPR/Cas9 are and dysfunction. The clinical trial status of different
the two most commonly used gene-editing methods. The targets in different tumors is detailed below (Table 1).
main targets of U-CAR-T cell clinical trials include CD19, Thirteen patients with hepatocellular carcinoma infused
BCMA, CD7, CD22, CD123, CS1, and mesothelin . with a median dose of 19.9 × 10 GPC3 CAR-T cells, eight
[66]
8
Allogeneic CD19 CAR-T cell by silencing T-cell receptor patients experienced Grade 1 – 2 CRS without Grade 3 –
α constant (TRAC) was first reported in 2012 . TALEN- 4 neurotoxicity, two patients achieved partial responses
[67]
edited CD19 CAR-T cells of CD52 /TCR killed target cells (PR), and one patient maintained a stable disease (SD) and
-
-
with high specificity . CRISPR/Cas9 editing of allogeneic was alive after 44.2 months . Six patients with metastatic
[68]
[72]
CAR-T cells with multiple genes has been reported, and pancreatic ductal adenocarcinoma received autologous
studies have shown that the product of pure CAR expression mesothelin-specific CAR-T cell infusion; none of them
is safe and efficient, and can direct CAR to the TRAC loci experienced CRS and neurotoxicity, two patients achieved
of TCR in T cells . Simultaneous CD52 knockdown in SD with progression-free survival times of 3.8 and
[69]
TCR gene-edited CAR-T cells, combined with CD52 5.4 months . Sixteen patients with metastatic pancreatic
[73]
monoclonal antibody, inhibited the immune cell activity in carcinoma were treated with 1 – 3 cycles of the epidermal
the host and enhanced the expansion of allogeneic CD19 growth factor receptor (EGFR)-CAR-T cells within
CAR-T cells, and produced an anti-leukemic effect . half a year, 4 of 14 evaluated patients achieved PR for 2
[70]
Volume 1 Issue 1 (2022) 6 https://doi.org/10.36922/gpd.v1i1.114