Page 119 - Bio Engineering Approaches to Cancer Diagnosis and Treatment

5.1 Adoptive cell-based therapy in combination with chemotherapy 117

5.1.2 Cancer therapy with TCR
Until 1990 ACT was limited to the infusion of lymphocytes to treat cancer and tumor
cells. In 1990 by the innovation of gene engineering a new sight opens to the devel-
opment of this technique [2].
On T cell surface there is an α- and a β-chain which noncovalently associated
with the CD3 as a TCR. Activation of the receptor has happened once the TCR
detects peptides bound to MHC of the surface of antigen-presenting tumor cells. And
by detection, the T cells can destroy them and inhibit the tumor cell expression [4].
The first TCR cancer immunotherapy has been tested against metastatic melanoma.
In this treatment scientists have used a TCR that bound to the human lymphocyte
antigen A2 (HLA-A2) from a melanocytic antigen that makes a higher active TCR,
targeting MART-1 (melanoma antigen recognized by T cell-1). This approach even
could detect the malignant cells with lower MART-1 expression [10]. Although the
development of this therapy using TCR was worthy, it also has other side effects
which were targeting normal melanocyte of skin, eye, cochlea, hence, some off-
tumor toxicity has happened in 50% of the patient who got this treatment. In others
TCR cancer-based therapies which were the targeting of antigen MAGE-A3, some
fatal neurotoxicity and cardiotoxicity have been observed, nonetheless, the treatment
with targeting antigen NY-ESO-1 for cancer of the testis, a clinical efficacy without
any cardiotoxicity has been reported [9]. This experiment has increased the hope to
make this technique as an efficient method. Engineered T cell and its entrance to the
CTR cancer therapy have shown that the production of specific T cells for particular
neo-antigens would be safer and efficient than the share antigen. However, these
ideas need clinical trials and lots of research to be done [2,4,10].

5.1.3 CAR T cell therapy
By the development of Gene-transfer techniques chimeric antigen receptor (CAR)
T cells as immune cancer therapy has been developed [10,11]. The advantage of
CAR is it combines antigen-binding domains and it has additional costimulatory
domains for receptors such as CD28, OX40, and CD137 [10,4]. The problem of other
techniques as they could not able to target tumor cells which represent less or does
not represent MHC. It means that it has overcome some limitations of TCR T cell
therapy which one of them was the need for MHC expression for tumor cells [12].
Kuwana and Eshhar [13,14] were the first group who have shown that these synthetic
receptors molecules are independent of MHC for targeting. This property has been
known as one of the best advantages of CAR T cells. Therefore, CAR T cells can
kill many tumors cells and promote immune surveillance to prevent tumor recur by
adaptive immunity (Table 5.1).
CAR T cells technique provides a broad development in cancer immune therapy.
At first it only has been used in the treatment of leukemia and lymphoma but nowa-
days, with the help of engineered T cells and genetic editing treatment, it has gone far
away from oncology and it has also entered the application of organ transplantation
and treatment of autoimmunity [12].