*4.2.4 Regulatory guidelines and cost*

Regulatory guidelines are other part of the story that limit the use of any therapy where biological samples are used for therapeutic. There are certain considerations to be followed for minimal manipulation and homologous use of human cells, tissues, and cellular and tissue-based products. Cellular & Gene Therapies are complex products which are regulated by the Food and Drug Administration (FDA) in the United States. The European Union (EU), governs the regulation of all medicinal products for human use, including advanced therapy medicinal products (ATMPs), i.e., medicinal products comprised of cells, genes, or tissues to ensure the quality, safety, and efficacy of medicines placed on the market in the EU. The aims of EU are to ensure the quality, efficacy and most importantly safety of public health.

A very high treatment cost of ACT based immunotherapies has been another concern for its limited use [20, 63]. Cost of CAR-T cell has been curtailed by developing Universal CAR-T cell and CAR NK cell so that this therapy can be a hope for majority of cancer patients [64].

#### **4.3 Advantages**

There are many advantages with ACT that outweigh the conventional therapy. One major advantage of TCR-T cell therapy is that it can target many TAA, even when these lie intracellular and are deep seated. Site directed injection of T cells into tumor giving superior result than systemic administration, is yet another favorable approach in cell-based therapies. A successful example of such application is reported in brain tumors where T cells are injected into CSF directly [43, 54]. Similarly, next generation of CARs have enhanced the ability of T cells to destroy tumor by infiltrating into diseased tissue site and have potential to moderate tumor microenvironment by secreting pro-inflammatory cytokines and expand their own life span *in-vivo* [64]*.*

CARs have another unique ability to recognize not only peptide but also carbohydrate and glycolipid antigens, thus increasing their target antigen number and are also not MHC restricted.
