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4.4 Chemo immunotherapy 87

using these therapies. However, the chemotherapy regimens which have been used
with low doses of drugs reduce the number of T cells which cause the formation
reg
of an immune environment in the tumor and will ultimately lead to the cancer cells
death. However, the use of high-dose regimens which are recommended for some
advanced cancers is immunosuppressive and will inevitably lead to the ineffective-
ness of chemotherapy. Therefore, the use of low-dose chemotherapy regimens can
be effective in stimulating the immune system to fight against tumor cells. However,
it is not possible to use low-dose regimens in all cases, because of the progression
of the disease. Additionally, the stimulatory effect of low-dose chemotherapy drugs
on the immune system may not be enough in some cases. Therefore, the use of che-
motherapy in combination with immunotherapy as an effective therapeutic treatment
for systemic malignancies has been considered. In fact, immunotherapy removes
parts of the tumor that are resistant to chemotherapy and those that likely to cause
metastasis [48].

4.4.2.1 Mechanisms of chemo immunotherapy
The main pathway of chemo immunotherapy that is more widely considered is the
use of chemical agents conjugated to monoclonal antibodies. Through these antibod-
ies, the chemical agents have been specifically introduced into cancerous cells, and
not only do they prevent the side effects of chemotherapy, but the highest amount of
the dose injected into cancer cells is also reached. The monoclonal antibodies and
their performance are discussed in detail in the previous chapters. The use of small
molecular inhibitors is another mechanism of chemotherapy which work by block-
ing some signaling pathways, preventing abnormal cells from being removed by the
physiological system of the body, eliminates abnormal cell proliferation and prevents
the disease from reversing.
In general, chemo immunotherapy treatment against cancer occurs in two ways:

1. Causing the apoptosis of primary tumor cells by chemical agents that
specifically target cancer cells, and then introducing tumor cell antigens to the
immune system to prevent recurrence of the disease.
2. Destruction of tumor cells caused by chemical agents and changes in the
signaling pathways of cancer cells to prevent recurrence of the disease [49].
To date, many chemo immunotherapy regimens have been investigated and
clinically examined. One of the most famous chemo immunotherapies is CHOP
(Cyclophosphamide, Hydroxydaunorubicin, Oncovin, and Prednisone) combined
with RITUXIMAB, and this is used to treat B-cell non-Hodgkin lymphomas [50].

4.4.3 Clinical examination of chemo immunotherapy
In 2016, Fischer et al. has compared two therapeutic methods for the treatment of
chronic lymphocytic leukemia (CLL) in a clinical study. They compared the Fluda-
rabine and Cyclophosphamide (FC) regimen with Fludarabine, Cyclophosphamide
and Rituximab (FCR) regimen on patients with CLL, and have shown that FCR was