Kinetics of rebounding of lymphoid and myeloid cells in mouse peripheral blood, spleen and bone marrow after treatment with cyclophosphamide

Salem, Mohamed L.; Al-Khami, Amir A.; El-Nagaar, Sabry A.; Zidan, Abdel‐Aziz A.; Al-Sharkawi, Ismail M.; Díaz-Montero, C. Marcela; Cole, David J.

doi:10.1016/j.cellimm.2012.03.010

Cited by 38 publications

(31 citation statements)

References 34 publications

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“…Of note, the duration of Treg depletion was longer after melphalan treatment compared to CTX treatment. Consistent with published data (38, 39), we showed that CTX treatment led to an initial reduction followed by rebound and expansion of innate immune cells (Fig. 1C), including monocytes (CD11b + Ly6C hi Ly6G − ), granulocytes/neutrophils (CD11b + Ly6C int Ly6G hi ), macrophages (CD11b int F4/80 + ), conventional DCs (CD11c + MHCII + ) and plasmacytoid DCs (CD11c int B220 + PDCA1 + ).…”

Section: Resultssupporting

confidence: 92%

Alkylating Agent Melphalan Augments the Efficacy of Adoptive Immunotherapy Using Tumor-Specific CD4+ T Cells

Ding

Cao

et al. 2015

The Journal of Immunology

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In recent years the immune-potentiating effects of some widely used chemotherapeutic agents have been increasingly appreciated. This provides a rationale for combining conventional chemotherapy with immunotherapy strategies to achieve durable therapeutic benefits. Previous studies have implicated the immunomodulatory effects of melphalan, an alkylating agent commonly used to treat multiple myeloma, but the underlying mechanisms remain obscure. In the current study, we investigated the impact of melphalan on endogenous immune cells as well as adoptively transferred tumor-specific CD4+ T cells in tumor-bearing mice. We showed that melphalan treatment resulted in a rapid burst of inflammatory cytokines and chemokines during the cellular recovery phase after melphalan-induced myelo-leukodepletion. After melphalan treatment, tumor cells exhibited characteristics of immunogenic cell death, including membrane translocation of the endoplasmic reticulum resident calreticulin (CRT), and extracellular release of high-mobility group box 1 (HMGB1). In addition, there was enhanced tumor antigen uptake by dendritic cells in the tumor-draining lymph node. Consistent with these immunomodulatory effects, melphalan treatment of tumor-bearing mice led to the activation of the endogenous CD8+ T cells, and more importantly, effectively drove the clonal expansion and effector differentiation of adoptively transferred tumor-specific CD4+ T cells. Notably, the combination of melphalan and CD4+ T-cell adoptive cell therapy (ACT) was more efficacious than either treatment alone in prolonging the survival of mice with advanced B-cell lymphomas or colorectal tumors. These findings provide mechanistic insights into melphalan’s immunostimulatory effects, and demonstrate the therapeutic potential of combining melphalan with adoptive cell therapy utilizing antitumor CD4+ T cells.

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Section: Resultssupporting

confidence: 92%

Alkylating Agent Melphalan Augments the Efficacy of Adoptive Immunotherapy Using Tumor-Specific CD4+ T Cells

Ding

Cao

et al. 2015

The Journal of Immunology

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“…8,32 In this study we found that Tregs were significantly reduced in combination treated tumor-bearing mice 4 d after mCPA treatment end, but since the total levels of CD4 C T cells were also reduced at this time point we could not conclude that the Treg reduction was selective. Total Tregs were comparable in all groups by day 8 (Fig.…”

Section: E953407-10 Volume 3 Issue 8 Oncoimmunologymentioning

confidence: 60%

“…The sensitivity of B cells toward various doses of cyclophosphamide treatment is well known, but the participation of B cells in vaccine-induced antitumor immune responses is not well defined. 32,33 A suppressor subset of B cells, referred to as regulatory B cells or B10 and recently identified as CD19 C CD5 C CD1d hi , may play a role in fostering tumor progression. 34,35 B cells in general may play an underappreciated role in promoting tumor growth, as B-cell deficiency results in slower tumor growth in some cancer models.…”

Section: E953407-10 Volume 3 Issue 8 Oncoimmunologymentioning

confidence: 99%

“…Increased occurrence of CD11b C / GR-1 hi MDSCs after low dose CPA treatment has been previously reported, leading to the suggestion that low dose CPA may be limited as a monotherapy because it stimulates accumulation of MDSCs that ultimately leads to rebounding of tumor growth. 32,41 To compensate, low dose CPA treatment has been combined with drugs that specifically reduce MDSC levels such as gemcitabine or ATRA. [42][43][44] We found that the combination of mCPA plus DPX-R9F did not increase MDSC levels, negating the need for additional drugs.…”

Section: E953407-10 Volume 3 Issue 8 Oncoimmunologymentioning

confidence: 99%

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Metronomic cyclophosphamide enhances HPV16E7 peptide vaccine induced antigen-specific and cytotoxic T-cell mediated antitumor immune response

et al. 2014

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In clinical trials, metronomic cyclophosphamide (CPA) is increasingly being combined with vaccines to reduce tumor-induced immune suppression. Previous strategies to modulate the immune system during vaccination have involved continuous administration of low dose chemotherapy, studies that have posed unique considerations for clinical trial design. Here, we evaluated metronomic CPA in combination with a peptide vaccine targeting HPV16E7 in an HPV16-induced tumor model, focusing on the cytotoxic T-cell response and timing of low dose metronomic CPA (mCPA) treatment relative to vaccination. Mice bearing C3 tumors were given metronomic CPA on alternating weeks in combination with immunization with a DepoVax vaccine containing HPV16E749–57 peptide antigen every 3 weeks. Only the combination therapy provided significant long-term control of tumor growth. The efficacy of the vaccine was uncompromised if given at the beginning or end of a cycle of metronomic CPA. Metronomic CPA had a pronounced lymphodepletive effect on the vaccine draining lymph node, yet did not reduce the development of antigen-specific CD8+ T cells induced by vaccination. This enrichment correlated with increased cytotoxic activity in the spleen and increased expression of cytotoxic gene signatures in the tumor. Immunity could be passively transferred through CD8+ T cells isolated from tumor-bearing mice treated with the combinatorial treatment regimen. A comprehensive survey of splenocytes indicated that metronomic CPA, in the absence of vaccination, induced transient lymphodepletion marked by a selective expansion of myeloid-derived suppressor cells. These results provide important insights into the multiple mechanisms of metronomic CPA induced immune modulation in the context of a peptide cancer vaccine that may be translated into more effective clinical trial designs.

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“…5-Fluorouracil is an anticancer drug, whose toxicity can lead to cytopenias and diarrhea [41,42]. Most other anti-cancer drugs, such as cyclophosphamide and oxaliplatin, also have such side effects [43,44]. Some antibiotics, such as β-lactam-containing antibiotics, can induce cytopenias in patients with hepatic decompensation, which may be due to the abnormal liver metabolism caused by excessive β-lactam-containing antibiotics, leading to suppression of leukocyte precursor cells in the bone marrow [45].…”

Section: Drugs Toxicitymentioning

confidence: 99%

Non-Hypersplenism Causes of Peripheral Cytopenias in Patients with Cirrhotic Portal Hypertension: A Review

Lv¹,

Lau²,

Deng³

et al. 2016

J Hypertens (Los Angel)

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Hypersplenism and non-hypersplenism factors, either alone or in combination, can cause peripheral cytopenias in patients with cirrhotic portal hypertension. Although non-hypersplenism factors account for only a small proportion of patients, they do exist. When peripheral cytopenias do not improve, or fail to improve adquately, or even become worse after splenectomy in these patients, non-hypersplenism factors should be considered. This review aims to provide an overview of non-hypersplenism factors.

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Kinetics of rebounding of lymphoid and myeloid cells in mouse peripheral blood, spleen and bone marrow after treatment with cyclophosphamide

Cited by 38 publications

References 34 publications

Alkylating Agent Melphalan Augments the Efficacy of Adoptive Immunotherapy Using Tumor-Specific CD4+ T Cells

Alkylating Agent Melphalan Augments the Efficacy of Adoptive Immunotherapy Using Tumor-Specific CD4+ T Cells

Metronomic cyclophosphamide enhances HPV16E7 peptide vaccine induced antigen-specific and cytotoxic T-cell mediated antitumor immune response

Non-Hypersplenism Causes of Peripheral Cytopenias in Patients with Cirrhotic Portal Hypertension: A Review

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