**2. Emergence of ACT**

The concept of ACT was first developed more than fifty-five years back when immune lymphocytes were successfully used to inhibit growth of sarcoma in an animal model [21].

Further, efforts were made to augment the potential of ACT by inducing activation and proliferation of immune cells in use, which was achieved by the use of recombinant IL2. The IL-2 has been known to potentiate immunological functions and later, its use as T cell growth factor were also recommended [22].

In cell based or cellular therapy, autologous or allogenic stem cells, progenitor or primary cells were the choice of possible cell types, which were modified *ex-vivo* and transfused into the patient for disease regression [2, 18, 19]. Cellular therapy's outcomes were better studied in the case of cancer as it was easy to readout its regression and thus, cancer was chosen first for treatment by cellular therapy. However, lately, this strategy has also been tested for treating cardiovascular, neurological and bone diseases [23]. The choice of cells to develop immunotherapy was from innate and adaptive immune systems as these cells play a key role in controlling cancer progression [24].

Further, initial failures of cell- based therapy were reported due to the role of T cells as the mediators of allograft rejection and also due to the host immune inhibitory factors [2, 25]. Therefore, measures were taken prior to ACT such as use of syngeneic lymphocytes for transfer to minimize the failures of the same [25]. Thus, ACT was developed as a biomedical procedure where the immune cells of the cancer patient, which have high anticancer activity, are expanded, modified and returned to the patients [2, 18, 19].

During eighties, the antitumor activities were reported in cells like natural killer (NK) and lymphokine-activated killer cells [26–30]. These cells directly recognize antigens present on tumor cells and kill them, whereas T cells recognize tumor antigens when presented with major histocompatibility complex (MHC) [31]. However, each cell has different anti-tumor potential. With advancements in immuno-technologies, such as fluorescence activated cell sorter, molecular markers were assigned on various immune cells to define them properly [32, 33]. This led to the classification of lineages and subtypes of immune cells. Thus, selection of cells was made and this followed their manipulation *ex-vivo* for ACT.

So far various cell types such as stem cells, T cells, dendritic cells and NK cells from patients are successfully used and have shown promising results in cancer regression (**Figure 1**). Dendritic cells (DCs) regulate innate immune response and due to its nature of antigen presentation, it may induce adaptive response. Tumor antigen exposed DCs may play a critical role in enhancing cytotoxic activities of immune cells. Therefore, DCs are used as an anti-tumor therapeutic vaccines or to enhance the stimulation of cytotoxic T cells by appropriate antigen presentation [34].

Different subset of T cells (gamma/delta T cells, regulatory T cells, helper and cytotoxic T lymphocytes) respond differently for various tumor subtypes [35]. Interestingly, some T cell subtypes confer advantage over other in reducing tumor volume [36].
