Beyond DNA Damage: Exploring the Immunomodulatory Effects of Cyclophosphamide in Multiple Myeloma

Swan, Dawn; Gurney, Mark E.; Krawczyk, Janusz; Ryan, Aideen E.; O’Dwyer, Michael

doi:10.1097/hs9.0000000000000350

Cited by 33 publications

(25 citation statements)

References 109 publications

(204 reference statements)

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“…Many multiple myeloma standard-of-care drugs act directly by killing the tumor and remodeling the TME to break cycles of tumor survival. For example, the DNA-alkylating agent cyclophosphamide (Cy), in addition to inducing DNA damage, preferentially kills regulatory T cells (Treg), induces an acute secretory activating phenotype in tumor cells stimulating phagocytic activity, and promotes immunogenic tumor cell death (ICD), all of which can boost immunotherapy (16). Furthermore, thalidomide and derivatives ( immunomodulatory imide drugs, IMiD), also known as Cereblon (CRBN) modulators, have pleiotropic effects on the immune system that include upregulating cytokine production and potentiating growth and survival of effector T lymphocytes while reducing Treg expansion and function (17,18).…”

mentioning

confidence: 99%

Tumor Burden Limits Bispecific Antibody Efficacy through T-cell Exhaustion Averted by Concurrent Cytotoxic Therapy

Meermeier

Welsh

Sharik

et al. 2021

Blood Cancer Discovery

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Although chemotherapeutic agents and molecular medicine are pillars of successful treatment of cancer, the recent clinical development of immunotherapies shows compelling promise in the treatment of many tumor types. In hematologic malignancies, immunotherapies centered upon cytolytic T lymphocytes as drugs, such as chimeric antigen receptor (CAR)-T cells and bispecific T-cell engagers (BiTE) or antibodies (BsAb), are central among these advances. BiTEs and BsAbs are "offthe-shelf" drug therapies that circumvent the need for timeconsuming and expensive ex vivo manipulation of patient cells. These agents often consist of monoclonal antibodies or singlechain variable fragments in the case of BiTEs, engineered with one binding site directed toward a tumor-specific antigen and another against the T-lymphocyte activating receptor CD3epsilon. BsAbs redirect T cells to kill tumors by bringing them into physical contact and activating secretion of cytotoxic molecules (1). Due to their novel mode of action, BsAb therapeutics may provide an effective option for all patients, including those with cytogenetically high-risk or heavily pretreated disease that renders them more resistant to standard-of-care therapy.

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mentioning

confidence: 99%

Tumor Burden Limits Bispecific Antibody Efficacy through T-cell Exhaustion Averted by Concurrent Cytotoxic Therapy

Meermeier

Welsh

Sharik

et al. 2021

Blood Cancer Discovery

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“…The alkylating agent cyclophosphamide has been used in the treatment of MM for over 60 years and, at low doses, it also presents significant immunomodulatory activity [ 193 ]. In this sense, treatment of different tumor models with mafosfamide (a chemical compound related to cyclophosphamide) or cyclophosphamide induces CALR translocation [ 181 , 182 ] and the release of HMGB1 [ 181 ], both of them being surrogate ICD markers.…”

Section: Drugs With Immune-stimulating Activity In Multiple Myelommentioning

confidence: 99%

Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression

Díaz-Tejedor

Lorenzo-Mohamed

Puig

et al. 2021

Cancers

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Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterations in the expression of surface molecules are also responsible for immunosuppression. In this scenario, immunotherapy, as is the case of immunotherapeutic monoclonal antibodies (mAbs), aims to boost the immune system against tumor cells. In fact, mAbs exert part of their cytotoxic effects through different cellular and soluble immune components and, therefore, patients’ immunosuppressive status could reduce their efficacy. Here, we will expose the alterations observed in symptomatic MM, as compared to its precursor stages and healthy subjects, in the main immune populations, especially the inhibition of effector cells and the activation of immunosuppressive populations. Additionally, we will revise the mechanisms responsible for all these alterations, including the interplay between MM cells and immune cells and the interactions among immune cells themselves. We will also summarize the main mechanisms of action of the four mAbs approved so far for the treatment of MM. Finally, we will discuss the potential immune-stimulating effects of non-immunotherapeutic drugs, which could enhance the efficacy of immunotherapeutic treatments.

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“…While the alkylating effect is predominant when cyclophosphamide is used at high doses, more recent studies have observed that cyclophosphamide at lower doses, also described as metronomic dosing, has significant immunomodulatory activity [ 62 , 63 ]. Although there is no clear borderline between low and high doses, new roles for the metronomic use of cyclophosphamide are being explored in the context of immune-mediated therapies, particularly immunomodulating agents.…”

Section: Current Use Of “Old” Alkylating Agentsmentioning

confidence: 99%

Current and Novel Alkylators in Multiple Myeloma

Schjesvold

Oriol

2021

Cancers

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A large number of novel treatments for myeloma have been developed and approved; however, alkylating drugs continue to be part of standard regimens. Additionally, novel alkylators are currently being developed. We performed a non-systematized literary search for relevant papers and communications at large conferences, as well as exploiting the authors’ knowledge of the field, to review the history, current use and novel concepts around the traditional alkylators cyclophosphamide, bendamustine and melphalan and current data on the newly developed pro-drug melflufen. Even in the era of targeted treatment and personalized medicine, alkylating drugs continue to be part of the standard-of-care in myeloma, and new alkylators are coming to the market.

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Beyond DNA Damage: Exploring the Immunomodulatory Effects of Cyclophosphamide in Multiple Myeloma

Cited by 33 publications

References 109 publications

Tumor Burden Limits Bispecific Antibody Efficacy through T-cell Exhaustion Averted by Concurrent Cytotoxic Therapy

Tumor Burden Limits Bispecific Antibody Efficacy through T-cell Exhaustion Averted by Concurrent Cytotoxic Therapy

Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression

Current and Novel Alkylators in Multiple Myeloma

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