1.     
Introduction

Over the years cancer treatment mainly involves
three common strategies: chemotherapy, surgical intervention or using
radiotherapy or eradicate cancerous tumour. Immunotherapy has lately emerged as
a fourth strategy to counter cancer. It involves targeting cancer cells through
tumour specific immune cells. These immune cells selectively target the tumour
cells by distinguishing them from normal healthy cells of the body.

The advantage of using T Cells immunotherapy is that
because it utilises antigens for recognistion hence it can target metastatic
cancer cells aswell. Furthermore, as T cells have memory hence it maintains
therapeutic efficacy for many years post immunotherapy.

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Adoptive cell therapy (ACT) involves the use of
lymphocytes which are specific for a tumour type. These tumour specific
lymphocytes are obtained from patient blood or from tumour cells and their
expansion and activation is done ex vivo thereby they are infused back into the
patient or polyclonal peripheral T-cells are modified genetically by
incorporating a tumour specific receptor in order to generate tumour specificity
for the immunotherapy (1-3).

 

1.1  Hisorical background of ACT

The first T lymphocytes function was elucidated in
the 1960s where it was ascertained in experiemental animals models that
allograft rejection was mediated by the T lymphocytes. In those years the
expansion and manipulation of  T cells in
culture media was not possible so the T cells could not be used to treat
allograft murine tumours.

In small sized tumors slight inhibition of tumor
growth was observed by the use of syngenic lymphocytes which were highly immunized
against the tumor cells (4, 5). It was suggested in preclinical
studies that the host inhibitory factors have a role to play in this and
chemotherapy or radiation before transfer of cells caused depletion of
lymphocytes so it enhanced the ability of transferred T lymphocytes to treat
tumor cells through immunotherapy (6, 7).

In 1976 Interleukin-2 (IL-2) which is a T cell
growth factor was described for the first time. This provided an opportunity to
grow T lymphocites ex vivo without affecting the effector functions of the
lymphocytes hence paving way for ACT (8). High doses of  IL-2 when administered directly in mice
inhibited the tumour growth (9), and subcutaneous lymphomas were
successfuly treated by immune lymphocytes which underwent prior IL-2 expansion
before intravenous injection (10). The
therapeutic potential of these lymphocytes was enhanced by the addition of IL-2
post cell transfer (11). In some patients of metastatic
melanoma administration of IL-2 could effectively cause longterm regression in
tumour mass (12). This gave an impetus for the the
specific T cells and their respective antigens identification for these cancer
immunotherapeutic agents. The main source of lymphocytes which were capable of recognising
tumor in vitro were the ones infiltrating in the stroma of growing,
transplantable tumours. The transfer of these adoptive syngenic tumor
infiltrating lymphocytes which were expanded in IL-2 could regress liver and
lung tumors in murine models (13). Tumor
infiltrating lymphocytes from melanomas showed that these contained specific cells
which had the capability to selectively recognise tumors which were autologous (14). In 1988 it was
demonstrated for the first time that adopted cell therapy by the use of
autologous tumour infiltrating lymphocytes in metastatic melanoma patients
could cause significant regression of cancer (15).

In mature culture cells of  Tumour infiltrating lymphocytes (TILs) the
main population of cells is of  CD8+
and CD4+ T cells. In cancer patients the propencity of T lymphocytes
to induce regression of tumor gave first insight into cancer immunotherapy in
humans. But, a fundamental issue was that the TILs were almost inexistent in
the blood circulation just after few days of injection and the duration of
action was very short. Improvement in ACT therapy for the treatment of cancer
was first observed in 2002 where it was observed that non-myeloablative
chemotherapy given before TILs injection could cause lymphodepletion which
resulted in increased efficacy of immunotherapy with significant improvement in
cancer regression and in some patients 80 % of the CD8+  of the injected TILs were found
circulating in the blood even after months post administration (16).

 

1.2  Adoptive Cell Therapy with T-Cells

Adotive cell therapy resulted in
78 % remission in chronic lymphoblastic leukemia patients as observed in
initial clinical trials (17, 18). Although these
are encouraging results in initial clinical finding but the effects of ACT in
solid tumours is not very promising, for instance the reponse rate in
metastatic melanoma patients is only 22 % (19-22). These in vivo
results are the factors which limit the ACT and its overall effectiveness as
immunotherapeutic agent (23). In ex vivo the ACT T-cells
imparts vigorous effector response but in tumour microenvironment or in
lymphatic organs in vivo they rapidly undergo immune suppression. As a result
of a diverse set of immunosupression mechanisms in tumour tissue including the
incorporation of host immune cells causing suppression, production of immunosuppressive
factors inside tumour and due to the activation of negative signalling pathways
which are co-stimulatory (24) the ACT T-cells become non
functional before the eradication of the tumor (25).

 

 

1.3  Targeted molecular immunotherapy

 

To
deliver immune modulating drugs at a selective tumor or tumor involving lymph
nodes the challenge is to design such a therapeutic modality which is selective
and has minimum  systemic non specific
stimulation. To achieve targeted drug accumulation in tumor tissue post
systemic distribution employs a strategy involving drug conjugation with
specific tumor antigen ligand, antibody or other binding moiety. Pro-inflammatory
cytokines are fused with tumor associated antigen specific antibodies and this
facilitates the cytokines delivery at targeted tumour tissue. Cytokines can be
attached with C or N terminals of light or heavy chains of IgG molecules (Figures 1A and 1B) (26). Antigen
binding, Fc receptors interaction and taking part in complement cascade
functions of the antibodies are maintained in these orientations. As an alternate to this cytokines
can also be attached with single chain variable fragment (scFv) or fused with
diabodies to preserve the antigen binding property of the antibody. (Figure 1C–E). Binding of
tumor cells with leukocytes has been proposed as one of the mode of action of
the immunocytokines (27-30). The antibody interacts with
antigen presenting surface of tumor in case of the IL-2 immunocytokines while the
binding of IL-2 to the IL-2 receptor on natural killer cells and T lymphocytes
results in promoting effector function and proliferation in the
microenvironment of the tumor. The efficacy of immunocytokines is dependent on
the antibody-dependent cellular toxicity (ADCC) interaction of the component of
the antibody with the Fc receptor domain (31). Because of increased size and
recycling of the fusion protein in endocytes through the Fc neonatal receptor
the immunocytokines as compared to parent cytokine molecules have a longer half
life in blood (32). The safety of immunocytokines
is increased because they can be injected in much lower doses due to increase
in the blood half life (33).

Apart
from cytokine targeting to the microenvironment of the tumor, antibodies which
are tumor targeted have also been utilised to instigate innate immunity based
stimulatory signals to destroy the tumor. CpG DNA which is agonist of TLR9 when
conjugated with antibody which is directed against antigen mucin-1 of tumor
regressed tumor size through promotion of ADCC 
and Natural Killer (NK) cells activation in mouse model of pancreatic
cancer (34). In Her2 positive breast cancers
and in non-Hodgkin lymphoma CD20 cells are targeted through CPG-antibody
conjugates (35). EGFR and HER2 overexpressing
tumours have been  successfully targeted by
this approach along with other cytotoxic signals involving polycytosine/polyinosine
which is an agonist of TLR3. Aptamers are formulated which are bispecific and bind
with EGF of tumor and agonises CD137 (36). When these aptamers are
administered systemically they resulted in regression of tumor in tumor models
and their toxicity level was lower than anti-CD137 antibodies or CD137-binding
aptamers which are untargeted. Immunomodulators can be targeted to  tumors 
by the use of natural ligands for the tumor cells which overexpress receptors.
For instance melittin which promotes cystolic delivery, a ternary conjugate of
EGF and polyethylene glycol attached to polyethyleneimine backbone was binded
with polyribocytidylic acid (pIC) to tumor cells overexpressing  EGFR 
results in inflammation and apoptosis of the tumor tissue (37, 38).

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