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Alan Tseng



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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-20 - Phase I Trial of in Situ Vaccination with Autologous CCL21-Modified Dendritic Cells (CCL21-DC) Combined with Pembrolizumab for Advanced NSCLC (Now Available) (ID 1888)

      08:00 - 18:00  |  Author(s): Alan Tseng

      • Abstract
      • Slides

      Background

      Effective immunotherapy options are lacking for patients with advanced non-small cell lung cancer (NSCLC) who progress on a programmed cell death-(ligand)1 [PD-(L)1] inhibitor and for those that are epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement positive after progression on tyrosine kinase inhibitor (TKI) therapy. One potential approach to improve immune checkpoint efficacy in these patient populations is to promote cytolytic T cell infiltration into tumors. This can be accomplished via in situ vaccination with functional antigen presenting cells (APCs) which can take advantage of the full repertoire of tumor antigens and convert the tumor into a lymph node-like environment promoting both local and systemic T cell activation. The chemokine CCL21 promotes co-localization of naive T cells and dendritic cells (DCs) to facilitate T cell activation. Our preclinical studies and phase I trial of intratumoral (IT) administration of DC genetically modified to overexpress CCL21 (CCL21-DC) revealed augmentation of tumor antigen presentation in situ, resulting in effective T cell responses and systemic antitumor immunity. However, increased PD-L1 expression was observed in some patient tumors, suggesting that tumor-mediated impairment of T cell function may be forestalling a more robust antitumor response. Similarly, improved PD-(L)1 inhibitor efficacy may be possible with enhanced T cell infiltration and augmented APC function following IT CCL21-DC. Therefore, we are conducting a phase I trial, combining IT CCL21-DC with pembrolizumab in patients with advanced NSCLC that are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy.

      Method

      This is a phase I, single institution, non-randomized, dose-escalating, multi-cohort trial followed by dose expansion. A maximum of 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection and are either (1) EGFR/ALK wild-type after progression on a PD-(L)1 inhibitor or (2) EGFR/ALK mutant after progression on TKI therapy. Three IT injections of autologous CCL21-DC (days 0, 21, 42) will be concurrently administered with pembrolizumab, followed by q3wk pembrolizumab up to 1 year. Primary objective of dose escalation is safety and determination of maximum tolerated dose (MTD) of IT CCL21-DC (5x106, 1x107, 3x107) when combined with pembrolizumab. Primary objective of dose expansion is objective response rate (ORR) of CCL21-DC at MTD combined with pembrolizumab. Secondary objectives include adverse event profiling and determination of drug target activity by immune monitoring studies. This trial, NCT03546361, is currently open for enrollment.

      Result

      Section not applicable

      Conclusion

      Section not applicable

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-33 - Deep Phenotyping of Immune Populations Reveals Baseline Predictors of Pembrolizumab Efficacy in NSCLC on KEYNOTE-001 (Now Available) (ID 2292)

      09:45 - 18:00  |  Author(s): Alan Tseng

      • Abstract
      • Slides

      Background

      Medical treatment of lung cancer has irreversibly changed since the development of immune checkpoint inhibitors like pembrolizumab. However, immune biomarkers of efficacy are still lacking. Preliminary data in melanoma showed that a high baseline blood level of classical monocytes was associated with improved outcome in patients treated with programmed cell death-1 (PD-1) inhibitors. This led us to explore the immune landscape of non-small cell lung cancer (NSCLC) patients treated with pembrolizumab on KEYNOTE-001 using high-dimensional mass cytometry.

      Method

      We analyzed 38 advanced NSCLC patients treated with pembrolizumab on KEYNOTE-001 at UCLA. Mass cytometry (CyTOF) was performed on baseline peripheral blood mononuclear cells (PMBC). We used a panel of 31 antibodies defining major immune populations of myeloid cells (plasmacytoid and myeloid dendritic cells, myeloid-derived suppressor cells, classical and CD16+ monocytes), lymphoid cells (B cells, NK cells, TReg, γδ T-cells, sub-populations of CD4+ and CD8+ T-cells), selected co-stimulatory (CD28, ICOS, 41BB), co-inhibitory molecules (PD-1, PD-L1, TIM3, LAG3, CTLA-4) and cytotoxicity molecules (perforin, granzymeB). Unsupervised clustering combined with predictive regression model (Citrus algorithm, false discovery rate = 1%) was used to detect immune populations differing between patients that experienced an objective response on trial, as assessed by immune-related response criteria (responders) vs those that did not (non-responders). Classical manual gating (FlowJo software) was used to confirm the Citrus results.

      Result

      Among the 38 patients analyzed via CyTOF, 27 patients had sufficient viable cells for analysis. Citrus algorithm comparing responders (n=7) and non-responders (n=20) revealed significant frequency differences in specific subtypes of three immune populations: monocytes, CD4+ and CD8+ T-cells. Manual gating confirmed that responders (vs non-responders) had increased frequency (%CD45+) of classical monocytes perforin+ granzymeB+ (5.54% vs 2.55%, p=0.029), central memory CD4+ T-cells ICOS+ CD28+ PD1+ (1.29% vs 0.83%, p=0.06) and over-expression of 41BB (mean metal intensity (MMI)=0.15 vs MMI=0.09, p=0.006) and perforin (MMI=108.4 vs MMI=70.7, p=0.004) in effector memory CD8+ T-cells.

      Conclusion

      Mass cytometry in the blood reveals that a high baseline frequency of activated and cytotoxic monocytes, CD4+ and CD8+ T-cells predicted for pembrolizumab efficacy in advanced NSCLC. Preliminary analyses correlating immune cell populations and overall survival are ongoing and suggest a similar increase in the three immune cell populations found to be higher in responders vs non-responders.

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