Page 118 - Bio Engineering Approaches to Cancer Diagnosis and Treatment

116 CHAPTER 5 Cell therapy

based on this function of immune cells has been defined recently, which is known as
adoptive cell transfer (ACT) [1–3]. This technique is the convergence of the knowl-
edge from molecular biology and cellular immunology that in past decades has pro-
vided a new way for the treatment of cancer. Lymphocytes have played an important
role in immune cancer therapy, hence, ACT for cancer therapy relies on the ex vivo
generation of tumor-specific lymphocytes with high activity and their injection in
large numbers to the host. In a half-century, different preclinical models have shown
a successful ACT therapy not only for cancer therapy, in particular, melanoma but
also for other disorders such as GVHD [4]. The scientists have also shown how the
characteristic of lymphocytes is important for ACT. T cells, in particular cytotoxic T
cell (CD8 + T cells) are important in adaptive immunity that has a straight effect on
cancer cells and pathogen clearance [1].
Different reports have also indicated that how host immune environment is impor-
tant to increase the ACT efficiency. Researchers have manipulated it using immuno-
suppression and IL-2 with transferred T cells before any cell administration [4].
There are three forms of ACT which has been developed for cancer therapy: (1)
tumor-infiltrating lymphocytes (TILs), (2) T cell receptor (TCR) T cells, and (3)
CAR T cells which are explained below.

5.1.1 Cancer therapy with TIL
TIL is a form of cellular therapy for cancer ACT [5,2]. This technique is the older
form of ACTs using melanoma T cells. Melanoma was the first model that tumor-
reactive T cells could expand in vitro to a large number for ACT. Steven Rosenberg
was the first one who exposing tumor-derived lymphocytes to high dose IL-2 as an
effective cancer treatment for patients with refractory metastatic melanoma [6,7]. To
increase the effect of TIL, more studies have been done that in one of the patients
received cyclophosphamide in one dose before cell administration and the result
has shown that there was only 34% difference between patients given cyclophos-
phamide and not given that drug. Overall, all studies have indicated that the dura-
tion of responses is not more than one year and the survival after administration is
very brief [8]. Other studies such as the use of fludarabine with cyclophosphamide
have been done to change the method to increase the effect of the TIL, although in
some aspects they were successful, but with all changes ultimately the objective
response rate reached to 54%. However, the investigation has shown that with all
the amendments this technique still has some limitations including the preparation
of a large number of lymphocyte, the requirement for acute clinical management of
toxicities, patient selection bias, and infrastructure demand [9]. Nevertheless, yet in
patients with chemotherapy-refractory, TIL has a positive effect. Recently, different
reports have indicated that chemotherapy before the administration can increase the
response to adoptive immunotherapy with TIL [2]. More new techniques, such as
in vitro activation of costimulatory ligands or PD1+ with tumor-reactive TIL, have
led to getting a good result in a preclinical model of breast-ovarian and colorectal
cancer [2].