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|Ref Type||Journal Article|
|Authors||Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, Jiang S, Chang Q, Spring DJ, Sharma P, Zebala JA, Maeda DY, Wang YA, DePinho RA|
|Title||Effective combinatorial immunotherapy for castration-resistant prostate cancer.|
|Date||2017 03 30|
|Abstract Text||A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b+Gr1+) promote tumour initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of immune checkpoint blockade agents together with targeted agents that neutralize MDSCs yet preserve T-cell function. Here we develop a novel chimaeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumour activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when immune checkpoint blockade was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of interleukin-1 receptor antagonist and suppression of MDSC-promoting cytokines secreted by prostate cancer cells. These observations illuminate a clinical path hypothesis for combining immune checkpoint blockade with MDSC-targeted therapies in the treatment of mCRPC.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||prostate cancer||not applicable||Dactolisib + unspecified CTLA4 antibody + unspecified PD-1 antibody||Preclinical||Actionable||In a preclinical study, combination of myeloid-derived suppressor cell-targeting with BEZ235 and immune checkpoint blockade with anti-CTLA4 and anti-PD-1 antibodies resulted in synergistic inhibition of tumor growth and metastasis in transgenic mouse models of metastatic castration-resistant prostate cancer (PMID: 28321130).||28321130|
|Unknown unknown||prostate cancer||not applicable||Cabozantinib + unspecified CTLA4 antibody + unspecified PD-1 antibody||Preclinical||Actionable||In a preclinical study, combination of myeloid-derived suppressor cell-targeting with Cometriq (cabozantinib) and immune checkpoint blockade with anti-CTLA4 and anti-PD-1 antibodies resulted in synergistic inhibition of tumor growth and metastasis in transgenic mouse models of metastatic castration-resistant prostate cancer (PMID: 28321130).||28321130|