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H. Zheng



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    MINI 02 - Immunotherapy (ID 92)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI02.07 - Preclinical Rationale for a Phase I/II Study of Pembrolizumab (P) and Vorinostat (V) in Immune Therapy Naïve and Pretreated Stage IV NSCLC (ID 734)

      11:20 - 11:25  |  Author(s): H. Zheng

      • Abstract
      • Presentation
      • Slides

      Background:
      The WHO estimated that 1.6 million people died of lung cancer in 2012. Nivolumab, an anti-PD-1 immune checkpoint inhibitor, was FDA approved on March 4, 2015 for platinum-refractory, metastatic, squamous-cell NSCLC, based upon a RR to single agent nivolumab of ~15% and improved OS. Combinatorial strategies may enhance these outcomes. Increased tumor expression of T cell chemokines, such as CCL5 and CXCL10, is associated with a better response to immunotherapy. Furthermore, expression of T cell chemokines is strongly and positively associated with increased T cell infiltration and improved patient survival. Therefore, enhancement of expression of T cell chemokines may augment response to PD-1 blockade immunotherapy.

      Methods:
      FDA-approved oncology agents were utilized from the Approved Oncology Drugs Set (97 agents) from the Developmental Therapeutics program of NCI. LKR cells were plated in 96-well plates, and a viability assay was performed 48 hours after drug administration (Cell Counting Kit-8, Dojindo Laboratories). Mice were bred and housed in the animal facility at Moffitt Cancer Center. Cells were harvested in logarithmic growth phase after being cultured for less than 2 weeks. 1x10[6] LKR or 344SQ cells were injected s.c. and tumors were monitored for growth by measurements 2-3 times per week. Romidepsin was injected i.p. (2mg/kg) on days 14,16, and 18 after tumor inoculation. Anti-PD-1 was injected i.p. (300μg/mouse) on days 15, 17, and 19 after tumor inoculation. Relative tumor size between treatment groups was analyzed using the t test with Welch’s correction.

      Results:
      Histone deacetylase inhibitors (HDACi), including vorinostat, emerged as the only class of agents in a 97-drug screen capable of inducing expression of multiple T cell chemokines, including CCL5, CXCL9, and CXCL10, in mouse and human lung cancer cell lines and primary tumors. HDACi’s ability to induce T cell chemokine expression was dependent on both JAK-STAT and NF-kB pathways. HDACi (romidepsin) treatment of mice bearing LKR tumors did not substantially cause tumor shrinkage but significantly reduced growth (p<0.0001; final tumor volume). This effect of HDACi was completely T cell dependent. LKR tumor cells had low cell surface expression of PD-L1 but which was substantially increased by IFN-g. PD-1 blockade with mAb reduced tumor growth but rarely induced rejection. However, when PD-1 blockade was combined with HDACi, 9 out of 11 mice demonstrated complete tumor rejection. HDACi anti-tumor response correlated with T cell chemokine induction in tumors and greater presence of tumor-infiltrating lymphocytes (TILs). We next used a mouse tumor model (344SQ) that was relatively resistant to anti-PD-1 treatment. PD-1 blockade combined with HDACi significantly reduced growth of these tumors compared to untreated (p=0.0003), anti-PD-1 alone (p=0.01), or HDACi (p=0.004) alone treated mice.

      Conclusion:
      HDACi not only enhanced anti-tumor response against PD-1 blockade sensitive tumors (LKR), but also induced response against PD-1 blockade resistant tumors (344SQ). HDACi induces JAK-STAT and NF-kB dependent chemokine expression and may induce tumor-infiltrating lymphocytes. Thus, a Phase I/randomized Phase II clinical trial of vorinostat, an orally active, small molecule HDACi, plus pembrolizumab, an anti-PD-1 humanized monoclonal IgG4-kappa antibody, is planned in patients with immune therapy naïve and pre-treated metastatic NSCLC.

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