Virtual Library

Start Your Search

Jarushka Naidoo



Author of

  • +

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

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • +

      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): Jarushka Naidoo

      • 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.

      Only 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, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      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.

  • +

    OA03 - Systemic Therapies for SCLC: Novel Targets and Patients' Selection (ID 121)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • +

      OA03.07 - Immune-Related Adverse Events and Clinical Outcome to Anti PD-1 Axis Inhibition in SCLC: A Multicenter Retrospective Analysis (Now Available) (ID 2880)

      13:30 - 15:00  |  Author(s): Jarushka Naidoo

      • Abstract
      • Presentation
      • Slides

      Background

      Immune-checkpoint inhibitors (ICIs) have shown promising activity in only a fraction of patients with small cell lung cancer (SCLC), and factors associated with clinical benefit are not well characterized. The development of immune-related adverse events (irAEs) may correlate with benefit from immune checkpoint inhibitors (ICIs) among patients with cancer. Whether an association exists between irAE development and improved clinical outcomes to ICIs in small cell lung cancer (SCLC) is unknown.

      Method

      We retrospectively analyzed data from five participating academic centers: the Dana-Farber Cancer Institute, East Carolina University, Columbia University, Beth Israel Deaconess Medical Center, and Johns Hopkins University. Patients with SCLC who received at least one dose of a programmed death (ligand) PD-(L)1 inhibitor alone or in combination with a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor were included in this study. To account for the time-dependent nature of irAE onset and clinical benefit from immunotherapy, we identified patients with early irAEs (defined as those occurring within 6 weeks of ICI treatment initiation) and performed a landmark analysis at this time point.

      Result

      Among 157 patients treated with ICIs, 65 (41.4%) experienced at least one irAE. Median time to the first irAE onset was 28 days (IQR:15-56). Baseline clinicopathologic characteristics were well balanced between patients who developed irAEs and those who did not. Median tumor mutational burden (TMB) was significantly higher among patients with irAEs compared to those without (14.4 vs 8.4 mutations/megabase [mut/Mb], P <0.01). Patients who developed at least one irAE had a significantly higher objective response rate (26.3% versus 3.3%, P <0.001), and significantly longer median progression-free survival (mPFS, 4.1 vs 1.3 months, HR: 0.30 [0.20-0.43, P <0.001]) and median overall survival (mOS, 14.1 vs 2.9 months, HR: 0.32 [0.21-0.48], P <0.001). The proportion of patients who were progression-free at 6, 9, and 12 weeks was significantly higher in patients who developed early irAEs compared to those who did not develop early irAEs (6 weeks: 89.5% vs 69.5%, P =0.01; 9 weeks: 71.1% vs 40%, P =0.001; 12 weeks: 65.8% vs. 31.6%, P <0.001). The median TMB was also significantly higher in patients who developed early irAEs (14.5 vs 8.7 mut/Mb, P <0.01).

      Conclusion

      Patients with SCLC treated with ICIs who developed early irAEs had a higher TMB and enhanced antitumor responses compared to those who did not develop irAEs. Whether a higher TMB is associated with the development of irAEs remains to be determined mechanistically.

      Only 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, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      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.

  • +

    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
    • +

      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  |  Author(s): Jarushka Naidoo

      • 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.

  • +

    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
    • +

      P2.04-24 - Transcriptional Profiling of Neoantigen Specific T Cells in Resectable NSCLC Treated with Neoadjuvant Anti-PD-1 (Now Available) (ID 2357)

      10:15 - 18:15  |  Author(s): Jarushka Naidoo

      • Abstract
      • Slides

      Background

      Neoadjuvant nivolumab has a manageable safety profile and can be effective in patients with resectable non-small cell lung cancer (NSCLC). To characterize the immune response in these patients, we sought to evaluate the existence and dynamics of neoantigen specific tumor-infiltrating T cells and identify their molecular phenotype including co-inhibitory checkpoint expression.

      Method

      We evaluated peripheral blood and tumor infiltrating lymphocytes from seven patients treated with nivolumab. To identify neoantigen-specific T cell responses, we used MANAFEST (Mutation Associated Neoantigen Functional Expansion of Specific T cells), an assay we developed that links antigen specificity with unique CD8+ TCR Vβ CDR3 identities. We then carried out single cell TCRseq/RNAseq of tumor infiltrating T lymphocytes (TIL) to enumerate the genome wide digital gene expression and T cell clonotypic identity of each single cell (VDJ+DGE analysis), and particularly those with Vβ CDR3 regions identical to those identified as neoantigen-specific by MANAFEST.

      Result

      Neoantigen-specific TCRs were detected in peripheral blood in all 3 patients with major pathologic response (MPR) and in 3 of 4 patients without MPR. Several of these clonotypes were found in the resected tumor and underwent peripheral expansions upon PD-1 blockade. In one notable patient, MD043-011, MANAFEST detected a T cell clonotype specific for a CARM1 R208W mutation, despite this patient having no evidence of pathologic response. This neoantigen-specific clonotype represented 3.4% of TIL. Two years later, this patient recurred with a solitary brain metastasis. Single cell analyses of TIL in the primary lung lesion and brain metastasis revealed the same neoantigen-specific T cell clonotype was detected in the metastatic lesion. Strikingly, this clonotype exhibited a differential expression profile in the primary and recurrent lesion, with the clonotype in the primary tumor having an enrichment and upregulation of heat shock proteins indicating molecular stress and the clone in the metastatic lesion having an upregulation of checkpoint molecules, including CTLA4, TIM3, and LAG3. T cell cloning and validation experiments, as well as identification of transcriptional programs associated with MPR, are ongoing.

      Conclusion

      The coupling of MANAFEST with single cell VDJ+ DGE analysis enabled us to characterize antigen specific clonotypes after differential expansion using the TCR as a molecular barcode. The presence of alternate co-inhibitory immune checkpoints on neoantigen-specific TIL from non-responding tumors suggests a potential driver of resistance to anti-PD-1 in early stage NSCLC. Ultimately, this integrative approach may provide key insights in predicting and understanding clinical response to neoadjuvant PD-1 blockade in 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.