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Joshua Reuss



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    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
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      MA11.10 - Peripheral T Cell Repertoire Evolution in Resectable NSCLC Treated with Neoadjuvant PD-1 Blockade (Now Available) (ID 1999)

      14:00 - 15:30  |  Author(s): Joshua Reuss

      • Abstract
      • Presentation
      • Slides

      Background

      Neoadjuvant PD-1 blockade has emerged as a promising treatment for resectable NSCLC. The neoadjuvant setting provides a unique opportunity to examine temporal-spatial dynamics of the T cell repertoire in the peripheral and tumoral compartments in response to PD-1 blockade.

      Method

      T-cell receptor (TCR) repertoire dynamics and composition were assessed in matched tumor, normal lung, and longitudinal peripheral blood from 20 NSCLC patients treated with neoadjuvant nivolumab (NCT02259621) and were correlated with major pathologic response (MPR , ≤10% viable tumor in resected specimen) at the time of resection. Treatment-induced dynamics of activated T cell clonotypes were additionally evaluated using TCR sequencing (TCRseq) of flow-sorted PD-1+ T cell populations. To focus on the phenotype of on-treatment intratumoral T cell clones that were recruited from the periphery, combined single-cell RNAseq/TCRseq was performed on post-treatment tumors of 6 patients (3 MPR and 3 non-MPR).

      Result

      MPR was associated with a more clonal intratumoral TCR repertoire and greater clonotypic sharing between pre-treatment blood and post-treatment tumor bed relative to non-MPR. Peripheral repertoire remodeling in response to anti-PD-1 treatment correlated with increased tumor infiltration. Specifically, in patients with MPR, the post-treatment tumor bed was enriched with T cell clones that were peripherally expanded between 2-4 weeks after PD-1 blockade. Clonotypic tracking of the peripherally expanded clones revealed persistence of those clones in the periphery 1+ years following surgical resection and cessation of PD-1 blockade. Single-cell RNAseq/TCRseq analyses revealed distinct phenotypes of peripherally expanded TIL for patients with MPR, with upregulated gene programs associated with cytotoxicity and cytoprotective effects against oxidative stress. Long-term peripherally-persistent TILs had significant upregulation of genes including GZMK, DUSP2, NKG7, 4-1BB and down-regulation of CTLA-4, CXCL13 and PDCD1 as compared to short-lived clones.

      Conclusion

      Our findings support the notion that neoadjuvant checkpoint blockade expands anti-tumor T cell clones in the periphery that can accumulate in tumor bed, facilitate tumor regression, and promote clonotypic persistence in the periphery. Importantly, our data demonstrate the systemic effect of neoadjuvant PD-1 blockade and indicate that the periphery may be an underappreciated originating compartment of effective anti-tumor immunity.

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    P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.16-06 - Early Changes in Pulmonary Function Are Associated with Development of Pneumonitis in NSCLC Patients Receiving Immune Checkpoint Blockade (ID 526)

      09:45 - 18:00  |  Presenting Author(s): Joshua Reuss

      • Abstract

      Background

      Checkpoint inhibitor pneumonitis (CIP) is an immune-related adverse event of immune checkpoint inhibitors (ICI). Pulmonary function test (PFT) changes have been noted in patients receiving drugs such as bleomycin, and PFTs are routinely used to monitor for lung toxicity in such patients. We retrospectively analyzed PFTs in ICI-treated non-small cell lung cancer (NSCLC) patients to identify PFT changes associated with ICI use, and determine whether CIP modified this association.

      Method

      The study cohort included NSCLC patients who were treated with PD-(L)1 ICI as standard-of-care or part of a clinical trial at Johns Hopkins from 1/2007 - 7/2017 and had ≥1 PFT in the year preceding and/or following ICI initiation. The primary outcomes of interest were forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Linear regression based on generalized estimating equations (GEE) was used to evaluate changes overall and by CIP status (CIP+: Patients who develop CIP, CIP-: Patients who do not develop CIP).

      Result

      A total of 58 patients (43 CIP-, 15 CIP+) were included. Median age was 66y and 96% of patients were current/former smokers. 52% had adenocarcinoma and 45% had squamous histology. 75% had stage III/IV disease at initial diagnosis. Patients received single agent PD-(L)1 ICI (77%), ipilimumab+nivolumab (ipi/nivo) (12%), and novel PD-(L)1 ICI (10%). Compared to CIP- patients, CIP+ patients were more likely to have squamous histology (67% vs. 34%) and receive ipi/nivo (27% vs 7%). In the overall study cohort, ICI initiation was associated with a 0.335L reduction in FEV1 (95% CI: -0.713, 0.042), 0.747L reduction in FVC (-1.21, -0.28), and 0.061 increase in FEV1/FVC (0.006, 0.116) consistent with restrictive lung physiology. Compared to CIP- patients, CIP+ patients had a 0.35L (-0.724, 0.013) lower FEV1 and 0.516L (-1.06, 0.02) lower FVC, while FEV1/FVC did not differ (-0.07, 0.07). The rate of change of FEV1/FVC over time was significantly higher among patients with vs without CIP (p<0.05).

      Conclusion

      Our data suggest that initiation of PD-(L)1 ICI is associated with progressively restrictive lung function changes on PFTs (increased FEV1/FVC) irrespective of CIP development. Furthermore, our results indicate that patients who eventually develop CIP may have an altered respiratory physiology prior to ICI initiation, with longitudinal changes in lung function that differ when compared to CIP- patients who receive checkpoint blockade. To further characterize PFT changes associated with CIP, a prospective study assessing serial PFTs in NSCLC patients receiving ICIs is underway.