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The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy

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Cyclophosphamide is an alkylating agent belonging to the group of oxazaphosporines. As cyclophosphamide is in clinical use for more than 40 years, there is a lot of experience using this drug for the treatment of cancer and as an immunosuppressive agent for the treatment of autoimmune and immune-mediated diseases. Besides antimitotic and antireplicative effects, cyclophosphamide has immunosuppressive as well as immunomodulatory properties. Cyclophosphamide shows selectivity for T cells and is therefore now frequently used in tumour vaccination protocols and to control post-transplant allo-reactivity in haplo-identical unmanipulated bone marrow after transplantation. The schedule of administration is of special importance for the immunological effect: while cyclophosphamide can be used in high-dose therapy for the complete eradication of haematopoietic cells, lower doses of cyclophosphamide are relatively selective for T cells. Of special interest is the fact that a single administration of low-dose cyclophosphamide is able to selectively suppress regulatory T cells (Tregs). This effect can be used to counteract immunosuppression in cancer. However, cyclophosphamide can also increase the number of myeloid-derived suppressor cells. Combination of cyclophosphamide with other immunomodulatory agents could be a promising approach to treat different forms of advanced cancer.
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Cancer Chemother Pharmacol (2016) 78:661–671
DOI 10.1007/s00280-016-3152-1
REVIEW ARTICLE
The effect of cyclophosphamide on the immune system:
implications for clinical cancer therapy
Martina Ahlmann1 · Georg Hempel2
Received: 8 June 2015 / Accepted: 2 September 2016 / Published online: 19 September 2016
© Springer-Verlag Berlin Heidelberg 2016
agents could be a promising approach to treat different
forms of advanced cancer.
Keywords T cells · Oxazaphosphorines · Immune
reactivation · Immunosuppression
Introduction
Cyclophosphamide is one of the oldest anticancer drugs. It
was discovered as early as 1958 and introduced into cancer
therapy in 1959 [1]. It remains a mainstay in the therapy of
haematological malignancies including lymphoma and leu-
kaemia as well as of various epithelial tumours including
breast, ovarian and small-cell lung carcinomas [2]. In Ger-
many, the drug is approved for the therapy of ALL, CLL,
Hodgkin and non-Hodgkin lymphoma, plasmocytoma, breast
cancer, ovarian carcinoma, small-cell lung cancer, Ewing-,
osteo- and rhabdomyosarcoma and neuroblastoma [3].
The drug is applied in many conditioning regimens
before bone marrow transplantation for haematological
malignancies (AML, MDS) as well as for aplastic anaemia.
Besides cancer chemotherapy, other approved indications
are life-threatening events in autoimmune and immune-
mediated diseases as lupus nephritis, Wegener’s granulo-
matosis and multiple sclerosis.
Important side effects are leuco- and thrombocytope-
nia, anaemia, cardio- and bladder toxicity. To avoid haem-
orrhagic cystitis, MESNA (sodium 2-sulfanylethanesul-
fonate) must be administered before cyclophosphamide
administration to neutralise the toxic metabolite acrolein
in the urine. In addition, nephrotoxicity, cardiotoxicity
and liver toxicity occur. All these effects are highly dose
dependent. Cardiotoxicity is dose-limiting in high-dose
schedules of cyclophosphamide [4].
Abstract Cyclophosphamide is an alkylating agent
belonging to the group of oxazaphosporines. As cyclophos-
phamide is in clinical use for more than 40 years, there is a
lot of experience using this drug for the treatment of can-
cer and as an immunosuppressive agent for the treatment of
autoimmune and immune-mediated diseases. Besides anti-
mitotic and antireplicative effects, cyclophosphamide has
immunosuppressive as well as immunomodulatory proper-
ties. Cyclophosphamide shows selectivity for T cells and is
therefore now frequently used in tumour vaccination proto-
cols and to control post-transplant allo-reactivity in haplo-
identical unmanipulated bone marrow after transplantation.
The schedule of administration is of special importance for
the immunological effect: while cyclophosphamide can be
used in high-dose therapy for the complete eradication of
haematopoietic cells, lower doses of cyclophosphamide are
relatively selective for T cells. Of special interest is the fact
that a single administration of low-dose cyclophosphamide
is able to selectively suppress regulatory T cells (Tregs).
This effect can be used to counteract immunosuppression
in cancer. However, cyclophosphamide can also increase
the number of myeloid-derived suppressor cells. Combina-
tion of cyclophosphamide with other immunomodulatory
* Georg Hempel
georg.hempel@uni-muenster.de
Martina Ahlmann
martina.ahlmann@ukmuenster.de
1 Pädiatrische Hämatologie und Onkologie, Klinik für
Kinder- und Jugendmedizin, Universitätsklinikum Münster,
Albert-Schweitzer-Campus 1, A1, Münster, Germany
2 PharmaCampus, Klinische Pharmazie, Westfälische
Wilhelms-Universität Münster, Corrensstraße 48, 48149,
Münster, Germany
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... Glyceraldehyde 3-phosphate dehydrogenase (GAPDH; forward: 5'-ACCTTCACTCCTCCATCTT-3' , reverse: 5'-AGGTCACAGACACGGTTG-3') and 5.8S rRNA (forward: 5'-AACTCTTAGCGGTGGATCA-3' , Cyclophosphamide is widely used as an antineoplastic drug because of antireplicative and antimitotic properties (Emadi et al., 2009). Moreover, cyclophosphamide is also used in the treatment of organ transplants and autoimmune diseases through immunosuppressive effect (Ahlmann and Hempel, 2016). A previous study has shown that administration of cyclophosphamide reduced the proliferation of B and T cells, suppressed the activity of cytotoxic T lymphocyte and NK cells, and stimulated the imbalance of type 1 T helper/type 2 T helper (Th1/Th2) cells, thus resulting in sudden immunosuppression in tumor cells (Noh et al., 2019). ...
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... For example, low dose cisplatin and oxaliplatin increase the number of circulating CD4+ and CD8+ T cells, while high dose regimens decrease the size of lymphocyte in a mouse model of colon cancer (132). Metronomic low dose cyclophosphamide enhance anti-tumor immune response by selectively reducing the amount of Treg cells in tumor patients (133), while high dose cyclophosphamide completely eradicates the hemopoietic cell (134). In addition, a novel administration mode called mediumdose intermittent chemotherapy provokes a striking response depending on the activation of a sustaining anti-tumor immune response (66,135). ...
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