Reactive Myelopoiesis Triggered by Lymphodepleting Chemotherapy Limits the Efficacy of Adoptive T Cell Therapy

Innamarato, Patrick; Kodumudi, Krithika; Asby, Sarah; Schachner, Benjamin; Hall, MacLean; Mackay, Amy; Wiener, Doris; Beatty, Matthew; Nagle, Luz; Creelan, Ben; Sarnaik, Amod A.

doi:10.1016/j.ymthe.2020.06.025

Cited by 31 publications

(20 citation statements)

References 58 publications

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“…A recent study in a melanoma model showed that lymphodepleting chemotherapy pre-conditioning promoted peripheral immunosuppressive MDSCs, which limited persistence of tumor infiltrating T cells and resulted in greater disease progression. 27 While at later timepoints, Cy-mediated immunosuppression may contribute to tumor recurrences in our models, our data strongly support the early benefits of Cy pre-conditioning in re-shaping the tumor microenvironment to promote CAR T cell responses.…”

Section: Discussionsupporting

confidence: 74%

Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Immunity

Murad

Tilakawardane²,

Park³

et al. 2020

Preprint

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Chimeric antigen receptor (CAR) T cell therapy has led to impressive clinical responses in patients with hematological malignancies; however, its utility in patients with solid tumors has been limited. While CAR T cells for the treatment of advanced prostate cancer are being clinically evaluated and are anticipated to show bioactivity, their safety and the impact of the immunosuppressive tumor microenvironment (TME) have not been faithfully explored preclinically. Using a novel human prostate stem cell antigen knock-in (hPSCA-KI) immunocompetent mouse model and syngeneic murine PSCA CAR T cells, we performed analyses of normal and tumor tissues by flow cytometry, immunohistochemistry, and/or RNA sequencing. We further assessed the beneficial impact of cyclophosphamide (Cy) pre-conditioning on modifications to the immunosuppressive TME and impact on PSCA-CAR T cell safety and efficacy. We observed an in vivo requirement of Cy pre-conditioning in uncovering the efficacy of PSCA-CAR T cells in prostate and pancreas cancer models, with no observed toxicities in normal tissues with endogenous PSCA expression. This combination also dampened the immunosuppressive TME, generated pro-inflammatory myeloid and T cell signatures in tumors, and enhanced the recruitment of antigen-presenting cells, and endogenous as well as adoptively-transferred CAR T cells, resulting in long-term anti-tumor immunity.

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Section: Discussionsupporting

confidence: 74%

Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Immunity

Murad

Tilakawardane²,

Park³

et al. 2020

Preprint

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“…Besides autologous T cell suppression, MDSCs inhibit both the expansion and function of adoptively transferred T cells. A recent study reported that TILs infusion combined with lymphodepletion significantly increases CD11b + CD15 + LOX-1 + PMN-MDSCs, which suppress TILs proliferation and IFN-γ production in melanoma and NSCLC patients (Innamarato et al, 2020). IL-6 was demonstrated to motivate hematopoietic progenitor cells after lymphodepleting.…”

Section: Effect On Adoptive T Cell Therapymentioning

confidence: 99%

Myeloid-Derived Suppressor Cells: Implications in the Resistance of Malignant Tumors to T Cell-Based Immunotherapy

Shi

et al. 2021

Front. Cell Dev. Biol.

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T lymphocytes function as major players in antigen-mediated cytotoxicity and have become powerful tools for exploiting the immune system in tumor elimination. Several types of T cell-based immunotherapies have been prescribed to cancer patients with durable immunological response. Such strategies include immune checkpoint inhibitors, adoptive T cell therapy, cancer vaccines, oncolytic virus, and modulatory cytokines. However, the majority of cancer patients still failed to take the advantage of these kinds of treatments. Currently, extensive attempts are being made to uncover the potential mechanism of immunotherapy resistance, and myeloid-derived suppressor cells (MDSCs) have been identified as one of vital interpretable factors. Here, we discuss the immunosuppressive mechanism of MDSCs and their contributions to failures of T cell-based immunotherapy. Additionally, we summarize combination therapies to ameliorate the efficacy of T cell-based immunotherapy.

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“…Monocytic MDSCs are monocytes with little or no HLA-DR expression and reduced antigen-presenting capability (CD14 + HLA-DR lo/neg monocytes). In cancer MDSCs are important inhibitors of innate and adaptive anticancer immunity and decrease the efficacy of immune checkpoint inhibitors, CAR-T-cells and anti-cancer vaccines (65,66). Some data suggest sargramostim can reverse this immune suppression by up-regulating HLA-DR expression and reversing effects of MDSCs and Tregs (33,34,38,(67)(68)(69)(70).…”

Section: Anti-cancer Immune Modulationmentioning

confidence: 99%

Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?

Lazarus

Ragsdale²,

Gale

et al. 2021

Front. Immunol.

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BackgroundSargramostim [recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)] was approved by US FDA in 1991 to accelerate bone marrow recovery in diverse settings of bone marrow failure and is designated on the list of FDA Essential Medicines, Medical Countermeasures, and Critical Inputs. Other important biological activities including accelerating tissue repair and modulating host immunity to infection and cancer via the innate and adaptive immune systems are reported in pre-clinical models but incompletely studied in humans.ObjectiveAssess safety and efficacy of sargramostim in cancer and other diverse experimental and clinical settings.Methods and ResultsWe systematically reviewed PubMed, Cochrane and TRIP databases for clinical data on sargramostim in cancer. In a variety of settings, sargramostim after exposure to bone marrow-suppressing agents accelerated hematologic recovery resulting in fewer infections, less therapy-related toxicity and sometimes improved survival. As an immune modulator, sargramostim also enhanced anti-cancer responses in solid cancers when combined with conventional therapies, for example with immune checkpoint inhibitors and monoclonal antibodies.ConclusionsSargramostim accelerates hematologic recovery in diverse clinical settings and enhances anti-cancer responses with a favorable safety profile. Uses other than in hematologic recovery are less-well studied; more data are needed on immune-enhancing benefits. We envision significantly expanded use of sargramostim in varied immune settings. Sargramostim has the potential to reverse the immune suppression associated with sepsis, trauma, acute respiratory distress syndrome (ARDS) and COVID-19. Further, sargramostim therapy has been promising in the adjuvant setting with vaccines and for anti-microbial-resistant infections and treating autoimmune pulmonary alveolar proteinosis and gastrointestinal, peripheral arterial and neuro-inflammatory diseases. It also may be useful as an adjuvant in anti-cancer immunotherapy.

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Reactive Myelopoiesis Triggered by Lymphodepleting Chemotherapy Limits the Efficacy of Adoptive T Cell Therapy

Cited by 31 publications

References 58 publications

Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Immunity

Pre-conditioning Modifies the Tumor Microenvironment to Enhance Solid Tumor CAR T Cell Efficacy and Endogenous Immunity

Myeloid-Derived Suppressor Cells: Implications in the Resistance of Malignant Tumors to T Cell-Based Immunotherapy

Sargramostim (rhu GM-CSF) as Cancer Therapy (Systematic Review) and An Immunomodulator. A Drug Before Its Time?

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