Epigenetic induction of adaptive immune response in multiple myeloma: sequential azacitidine and lenalidomide generate cancer testis antigen‐specific cellular immunity

Toor, Amir A.; Payne, Kyle K.; Chung, Harold M.; Sabo, Roy; Hazlett, Allison F.; Kmieciak, Maciej; Sanford, Kimberly W.; Williams, David C.; Clark, William; Roberts, Catherine; McCarty, John M.; Manjili, Masoud H.

doi:10.1111/j.1365-2141.2012.09225.x

Cited by 39 publications

(33 citation statements)

References 41 publications

(43 reference statements)

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“…Aza therapy in patients with relapsed or refractory Hodgkin lymphoma resulted in a complete response to immune checkpoint inhibitors [63]. We have also reported that the use of Aza combined with the immune modulatory lenalidomide induced the expression of CTAs within tumor cells, and generated CTA-specific immune responses in patients with multiple myeloma [64]. Similar results were observed in a mouse model of experimental metastatic breast cancer [65].…”

Section: Epigenetic Targeting Of Tumor Cells For Immune Modulationsupporting

confidence: 55%

Conditioning neoadjuvant therapies for improved immunotherapy of cancer

Benson

Manjili

Habibi

et al. 2017

Biochemical Pharmacology

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Recent advances in the treatment of melanoma and non-small cell lung cancer (NSCLC) by combining conventional therapies with anti-PD1/PD-L1 immunotherapies, have renewed interests in immunotherapy of cancer. The emerging concept of conventional cancer therapies combined with immunotherapy differs from the classical concept in that it is not simply taking advantage of their additive anti-tumor effects, but it is to use certain therapeutic regimens to condition the tumor microenvironment for optimal response to immunotherapy. To this end, low dose immunogenic chemotherapies, epigenetic modulators and inhibitors of cell cycle progression are potential candidates for rendering tumors highly responsive to immunotherapy. Next generation immunotherapeutics are therefore predicted to be highly effective against cancer, when they are used following appropriate immune modulatory compounds or targeted delivery of tumor cell cycle inhibitors using nanotechnology.

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Section: Epigenetic Targeting Of Tumor Cells For Immune Modulationsupporting

confidence: 55%

Conditioning neoadjuvant therapies for improved immunotherapy of cancer

Benson

Manjili

Habibi

et al. 2017

Biochemical Pharmacology

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“…8–10 In MM patients, combining lenalidomide and the DNMTi azacytidine stimulated an adaptive immune response by inducing the expression of antigens. 11 DNMTi and HDACi induced MAGE-A3 expression in primary MM cells, thereby stimulating recognition by MAGE-A3 cytotoxic T lymphocytes (CTLs). 12 The HDACi valproic acid induced natural killer (NK) ligands in MM cells and potentiated NK cell-mediated lysis.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory effects

et al. 2018

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Immune evasion is an important driver of disease progression in the plasma cell malignancy multiple myeloma. Recent work highlights the potential of epigenetic modulating agents as tool to enhance anti-tumor immunity. The immune modulating effects of the combination of a DNA methyltransferase inhibitor and a histone deacetylase inhibitor in multiple myeloma is insufficiently characterized. Therefore, we used the murine immunocompetent 5T33MM model to investigate hallmarks of immunogenic cell death as well as alterations in the immune cell constitution in the bone marrow of diseased mice in response to the DNA methyltransferase inhibitor decitabine and the histone deacetylase inhibitor quisinostat. Vaccination of mice with 5T33 cells treated with epigenetic compounds delayed tumor development upon a subsequent tumor challenge. In vitro, epigenetic treatment induced ecto-calreticulin and CD47, as well as a type I interferon response. Moreover, treated 5T33vt cells triggered dendritic cell maturation. The combination of decitabine and quisinostat in vivo resulted in combinatory anti-myeloma effects. In vivo, epigenetic treatment increased tumoral ecto-calreticulin and decreased CD47 and PD-L1 expression, increased dendritic cell maturation and reduced CD11b positive cells. Moreover, epigenetic treatment induced a temporal increase in presence of CD8-positive and CD4-positive T cells with naive and memory-like phenotypes based on CD62L and CD44 expression levels, and reduced expression of exhaustion markers PD-1 and TIM3. In conclusion, a combination of a DNA methyltransferase inhibitor and a histone deacetylase inhibitor increased the immunogenicity of myeloma cells and altered the immune cell constitution in the bone marrow of myeloma-bearing mice.

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“…Odunsi et al [19] recently published their findings that a New York esophageal squamous cell carcinoma 1 (NY-ESO-1) targeting cancer vaccine combined with decitabine treatment resulted in enhanced immune responses in advanced platinum-resistant ovarian cancer. We have used a similar strategy utilizing the DNAMTi azacytidine (Aza) in combination with lenalidomide to increase CTA-specific immune responses to multiple myeloma in patients [20]. …”

Section: Introductionmentioning

confidence: 99%

DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer

Terracina

Graham

Payne

et al. 2016

Cancer Immunol Immunother

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Adoptive T cell immunotherapy is a promising approach to cancer treatment that currently has limited clinical applications. DNA methyltransferase inhibitors (DNAMTi) have known potential to affect the immune system through multiple mechanisms that could enhance the cytotoxic T cell responses, including: upregulation of tumor antigen expression, increased MHC class I expression, and blunting of myeloid derived suppressor cells (MDSCs) expansion. In this study, we have investigated the effect of combining the DNAMTi, decitabine, with adoptive T cell immunotherapy in the murine 4T1 mammary carcinoma model. We found that expression of neu, MHC class I molecules, and several murine cancer testis antigens (CTA) was increased by decitabine treatment of 4T1 cells in vitro. Decitabine also increased expression of multiple CTA in two human breast cancer cell lines. Decitabine-treated 4T1 cells stimulated greater IFN-gamma release from tumor-sensitized lymphocytes, implying increased immunogenicity. Expansion of CD11b + Gr1 + MDSC in 4T1 tumor-bearing mice was significantly diminished by decitabine treatment. Decitabine treatment improved the efficacy of adoptive T cell immunotherapy in mice with established 4T1 tumors, with greater inhibition of tumor growth and an increased cure rate. Decitabine may have a role in combination with existing and emerging immunotherapies for breast cancer.

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Epigenetic induction of adaptive immune response in multiple myeloma: sequential azacitidine and lenalidomide generate cancer testis antigen‐specific cellular immunity

Cited by 39 publications

References 41 publications

Conditioning neoadjuvant therapies for improved immunotherapy of cancer

Conditioning neoadjuvant therapies for improved immunotherapy of cancer

Epigenetic treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory effects

DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer

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