Start Your Search
MINI 02 - Immunotherapy (ID 92)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:P. Forde, S.J. Antonia
- Coordinates: 9/07/2015, 10:45 - 12:15, Four Seasons Ballroom F3+F4
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)
10:45 - 12:15 | Author(s): H. Zheng
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.
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 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.
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.
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.
Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.