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Boris Sepesi



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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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      MA11.09 - Increased Frequency of Bystander T Cells in the Lungs Is Associated with Recurrence in Localized Non-Small Cell Lung Cancer (Now Available) (ID 955)

      14:00 - 15:30  |  Author(s): Boris Sepesi

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer (NSCLC) exhibits a high mutational burden. As a result, patients afflicted by this tumor type experience greater responses to immune checkpoint blockade. This is largely due to the ability of T cells to destroy tumor cells on the basis of antigens recognized by their T cell receptor (TCR). However, the lungs are exposed to carcinogens and pathogens which can also trigger a T cell response distinct from cancer. Therefore, a better understanding of the T cell repertoire in the lungs is needed to improve upon the success of current immunotherapies in NSCLC.

      Method

      We obtained peripheral blood, tumors, and adjacent uninvolved lungs from a cohort of 236 early stage NSCLC patients. Whole exome sequencing, RNA microarray, immunohistochemistry (CD3, CD4, CD8, CD57, CD68, FoxP3, CD45RO, GzmB, PD-1, and PD-L1) and T cell repertoire sequencing were performed in NSCLC patients and lungs from organ donors and COPD patients. Antigen specificity was predicted using the Grouping of Lymphocyte Interactions by Paratope Hotspot (GLIPH) algorithm. Single cell TCR and RNA sequencing as well as sequencing of the virome are underway.

      Result

      Clonality was associated with CD8 T cells (r=0.31; p=0.0003), GzmB (r=0.29; p=0.001) and IFN-γ (r=0.52; p<0.0001) production as well as with tumor mutational burden (r=0.19; p=0.015), HLA-B (r=0.29; p=0.0005) and β2-m expression (r=0.20; p=0.018). Patients with classical EGFR mutations exhibited lower T cell clonality (p=0.003) even after adjustment for TMB, highlighting the impact of this driver mutation on the T cell response. Surprisingly, clonality was higher in the adjacent uninvolved lung than tumor (p<0.0001), suggesting an active antigenic response outside the tumor. Comparison of the composition of the T cell repertoire between the uninvolved lung and tumor revealed 57% of the top 100 T cells in the tumor were also found in the adjacent normal lung, highlighting certain parallels in the ongoing antigenic responses. Deeper analysis suggested that shared T cells may have been reactive against mutations shared between the normal lung and tumor (r=0.23, p=0.028) or viruses (p<0.0001). Accordingly, patients with a more reactive T cell repertoire outside the tumor (i.e. bystanders) exhibited shorter disease-free survival (p=0.036) suggesting these responses against shared mutations and/or viruses may detract from the anti-tumor T cell response.

      Conclusion

      Our findings highlight the importance of understanding the specificity of the T cell repertoire in the lungs in patients with NSCLC treated with immunotherapy. As a high proportion of bystander T cells appear to reside in the lungs, their reactivation could contribute to the impaired responses and/or increased toxicity observed in certain patients with NSCLC treated with immunotherapy.

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    OA13 - Ideal Approach to Lung Resection and Novel Perioperative Therapy (ID 146)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      OA13.06 - Surgical Outcomes Following Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Non-Small Cell Lung Cancer - NEOSTAR Study (Now Available) (ID 2041)

      11:30 - 13:00  |  Presenting Author(s): Boris Sepesi

      • Abstract
      • Presentation
      • Slides

      Background

      Surgical outcomes following neoadjuvant immune checkpoint inhibitors (ICIs) are limited. We report 90-day perioperative results of the NEOSTAR phase II trial of neoadjuvant nivolumab or nivolumab/ipilimumab in resectable non-small cell lung cancers (NSCLCs).

      Method

      44 pts with stage I-IIIA NSCLC (AJCC 7th) were randomized to nivolumab (3 mg/kg IV, days 1, 15, 29, n=23) or nivolumab/ipilimumab (1 mg/kg IV, day 1, n=21) with resection planned between 3-6 weeks after last dose. Surgical approach and extent of resection were at surgeons’ discretion.

      Result

      39 (89%) patients underwent R0 resection, of those 2 (5%) were resected off trial after additional induction chemotherapy (1 nivolumab, 1 nivolumab/ipilimumab). Among 37 patients, 21 underwent surgery following nivolumab and 16 following nivolumab/ipilimumab. Median age 66 (43-83) years, 24 (65%) male, 33 (89%) white, 22 (59%) adenocarcinoma, 22 (59%) stage I, 9 (24%) stage II, 6 (16%) stage IIIA.

      5 (11%) were not resected, 1 (1/23, 4%) after nivolumab (stage II), 4 (4/21, 19%) after nivolumab/ipilimumab (1 stage I, 1 stage II, 2 stage IIIA). Reasons for unresectability were change in surgeon’s judgement (n=2), toxicity (n=1), progression (n=1), and declining pneumonectomy (n=1). Median time to surgery was 31 days (range 21-87). 8 (22%) operations were delayed beyond 42 days, 5 after nivolumab/ipilimumab (5/16, 31%) and 3 after nivolumab (3/21, 14%).

      33 (89%) underwent lobectomy, 2 (5%) pneumonectomy, 1 (3%) segmentectomy and 1 (3%) wedge resection. 27 (73%) had thoracotomy, 7 (19%) thoracoscopy, 3 (8%) robotic approach. 2 (5%) were electively converted from thoracoscopy to thoracotomy. Median operative time was 147 minutes (71-315), median blood loss was 100cc (50-1000), and median length of stay was 4 days (1-18).

      Perioperatively, pulmonary complications occurred in 8 (22%) patients: 8 (22%) prolonged air leak, 2 (5%) pneumonitis/pneumonias, 1 (3%) empyema, and 1 (3%) bronchopleural fistula (BPF). 1 (3%) died from complications of BPF and steroid therapy for pneumonitis. 4 (11%) developed atrial fibrillation, 1 (3%) diarrhea, 1 (3%) ileus, and 1 (3%) transient ischemic attack.

      Surgeons subjectively judged 15/37 (40%) of operations to be more complex than usual with 7/37 (19%) lasting > 4 hours.

      Conclusion

      Following three cycles of neoadjuvant ICIs 89% of patients underwent complete R0 resection, including two patients who received additional induction chemotherapy off trial. Five marginally operable patients who didn’t proceed to resection, and one perioperative mortality highlight the importance of cautious patient selection for neoadjuvant ICIs in the management of operable NSCLC.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-11 - Depicting the Intra-Tumoral Viral and Microbial Landscape of Localized NSCLC Using Standard Next Generation Sequencing Data (ID 1126)

      09:45 - 18:00  |  Author(s): Boris Sepesi

      • Abstract
      • Slides

      Background

      Studies from our group and others have shown that bacteria and viruses present in the tumor may impact therapeutic responses. In the specific context of non-small cell lung cancer (NSCLC), intra-tumoral viral DNA and bacteria have been reported previously to be linked to therapeutic outcomes. However, the interplay between intra-tumoral microorganisms and the host immune response in NSCLC remains unknown. Moreover, the prognostic and predictive therapeutic value of localized NSCLC-specific microbial composition has yet to be defined.

      Method

      RNA-sequencing (RNA-seq) (n=82) and whole exome sequencing (WES) (n=80) was performed on surgically resected (pTNM I-III) tumors from lung cancer patients enrolled in the ImmunogenomiC prOfiling of NSCLC (ICON) project. Intra-tumoral bacteria, viruses and fungi were queried with MetaPhlAn2, a bioinformatical analysis pipeline which employs unique clade-specific marker genes, using reads from RNA-seq and WES that did not map to the human genome/transcriptome. Generated data were correlated to patients’ clinicopathologic parameters as well as immune profiling using previously validated multiplex IHC panels based on Vectra 3.0™ multispectral microscopy IHC panels and image analysis (InForm™ 2.2.1 software).

      Result

      Our analyses revealed that 18.29% (n=15/82) of tumors contained bacterial signatures. The most frequent bacterial signature was related to Escherichia (n=9/15). Moreover, 6.49% (n= 5/77) of tumors had evidence of human viral signatures, including the Epstein-Barr virus (n=1/5). No tumors contained fungal signatures. Preliminary clinicopathologic analyses suggested that patients whose tumors harbor bacterial signatures had a trend towards decreased overall survival (p=0.12). Tumors from former smokers were also more likely to contain bacterial signatures (p=0.11). Preliminary multiplex immune cell IHC analyses did not highlight statistically significant associations with the presence of intra-tumoral bacteria.

      Conclusion

      Our results suggest that a significant proportion of localized NSCLC tumors may harbor components of the human microbiome. Further studies using larger cohorts and dedicated intra-tumoral microbiome and virome methodologies will be needed to better define these findings and to delineate associations with the local immune infiltrate.

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      P1.04-79 - CD73 Expression in Lung Adenocarcinomas and Immunological and Molecular Associations (ID 2412)

      09:45 - 18:00  |  Author(s): Boris Sepesi

      • Abstract

      Background

      Immune checkpoints inhibitors (ICI), in monotherapy or combination with chemotherapy, are the standard of care for lung adenocarcinoma (ADC) patients. Unfortunately, only a restricted number of patients will respond to ICI. Combination therapies such as CD73 inhibitors, are being studied with the goal to achieve synergic effects. CD73 is a membrane-bound protein with immunosuppressive functions. We previously reported that higher immune cell infiltration was associated mainly to CD73 basolateral (BL) expression, in this abstract, we show the correlation of CD73 expression at luminal (L) and BL membrane of ADC malignant cells (MCs), with annotated clinicopathological characteristics, immune and molecular biomarkers.

      Method

      CD73 IHC expression (clone D7F9A) was evaluated in 106 archived ADCs from patients that underwent surgical treatment without neoadjuvant therapy between February 1999 and February 2012 at MD Anderson Cancer Center (Houston, Texas, USA). We scored % and H-score of CD73 expression at the luminal (L) and basolateral (BL) membrane, we calculated the Total (T) CD73 as the average of L and BL, and classified ADCs in three groups: ‘T High’ (TH) (upper quartile for all tumors); ‘T Low’ (TL); ‘T Neg’ (TN) (<1%). We correlated T, L and BL expression and the three groups with clinicopathological characteristics, mutational status of KRAS and EGFR, TP53, STK11 and Tumor mutation burden (TMB), and cell densities of CD3, CD8, CD68, CD45RO, FOXP3, and Granzyme B, and PD-L1 expression (clone E1L3N) in MCs.

      Result

      T CD73 expression was found in 76%; BL in 60% and L in 57%; among ADCs with luminal membrane present (n=72), L CD73 was present in 83%. T+ and L+ expression was more frequent in never smokers (p=0.02 and p=0.003). Also higher frequency of L+ was found in older patients (>65) (p=0.01), tumors with non-solid histology patterns (p<0.001), EGFR mutation (p=0.048), non-mutated p53 (p=0.002), negative PD-L1 (p=0.03), and low TMB (<10 mut/MB) (p=0.001). Higher levels of L expression were found in KRAS mutated tumors (p=0.049). Higher BL expression positively correlated with p53 mutated tumors (p=0.038), PD-L1+ in MCs (p=<0.0001), and higher TMB (p=0.040).

      Our group analyses revealed that TH and TN were associated with ADCs from patients with >30 pack-year of smoking history (p=0.04), presence of any-solid histology pattern (p=0.03), p53 mutation (p= 0.005) and higher TMB (p=0.003) compared with TL. TH also had higher frequency of PD-L1+ tumors, and a higher cell density of CD3 (p=0.0001), CD8 (p=0.001), CD68 (p=0.048), CD45RO (p=0.036), FOXP3 (p=0.053), and Granzyme B (p=0.024) compared to TL and TN. TN showed higher frequency of STK11 mutation (p=0.034).

      Conclusion

      Based on the CD73 expression we defined subsets of lung adenocarcinomas that have distinct histological, molecular and immunological characteristics that may play a role in the response to ICI.

      Our characterization could help us to understand patient’s response to ICI, and identify patients that could potentially benefit from combination therapies.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-19 - Neoadjuvant Chemotherapy Is Associated with Immunogenic Cell Death and Increased T Cell Infiltration in Early-Stage NSCLC (ID 1122)

      10:15 - 18:15  |  Author(s): Boris Sepesi

      • Abstract
      • Slides

      Background

      Recent success using immune checkpoint blockade (ICB) in the metastatic setting has raised the need to understand the immune microenvironment (IME) in early-stage disease. Moreover, pre-clinical evidence suggests that cytotoxic agents can modulate this IME. A recent study conducted by our group showed that non-small cell lung cancer (NSCLC) patients who received neoadjuvant chemotherapy followed by surgery (NCT), as compared to patients who received upfront surgery (US), had higher densities of CD3+ lymphocytes and CD68+ tumor-associated macrophages (TAMs). CD3+CD4+ lymphocytes and TAMs also correlated with better clinical outcomes. In this study, we explored the relationships between NCT and the IME by harvesting tumor samples of multiple surgical NSCLC cohorts.

      Method

      The PROSPECT microarray database was queried in NCT (n=45) and US (n=200) patients to investigate differentially expressed genes related to immunogenic cell death (ICD), susceptibility to CD8+ T cell and NK cell cytotoxicity, priming of antigen presenting cells, immunosuppressive enzymes and intra-tumoral cytokines. Available data from the ImmunogenomiC prOfiling of NSCLC (ICON) and other surgical NSCLC cohorts was evaluated to determine: 1) differential immune profiling using FACS (NCT=17; US=39) and multiplex IHC imaging (NCT=10; US=72); 2) plasma circulating cytokines (NCT=18; US=73); 3) tumor mutational burden (TMB) (NCT=40; US=61). Participants who received NCT or US were excluded according to these criteria: 1) concurrent treatment in addition to NCT; 2) sarcomatoid and small cell histologies; 3) clinical or pathological TNM Stage 4 disease; 4) synchronous malignancies other than lung.

      Result

      PROSPECT NCT patients expressed increased damage-associated molecular pattern (DAMP) genes (HSPA2, HSPA4, HSPE1, and S100A2; p<0.05) and T cell-related chemotaxis and antigen presentation genes (CXCR7, CD1A; p<0.05). Concordantly, the ICON cohort FACS results showed that NCT patients display increases in: 1) infiltration of CD8+ T cells (p=0.004); 2) proliferating Ki67+CD8+ T cells (p=0.02); 3) tissue resident memory CD8+CD103+ (p=0.02) and CD4+CD103+ non-Treg cells (p=0.01). Trends from the ICON multiplex IHC also highlighted increases in CD8+ T cells (p=0.09), CD20+ cells (p=0.08), as well as PD-L1+ malignant cells (p=0.08) and PD-L1+ TAMs (p=0.08) in NCT patients, the latter finding being supported by increased circulating MCP-1 (p=0.03). TMB was similar between NCT and US groups (p=0.912).

      Conclusion

      Our data provides the first evidence of ICD (i.e., increased DAMP gene expression) following NCT in human early-stage NSCLC. Furthermore, our data highlights the association of NCT with a favorable IME (i.e., increased T cell infiltration), supporting the rationale of NCT and ICB combinations in localized NSCLC.

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      P2.04-90 - Nodal Immune Flare (NIF) Following Neoadjuvant Anti-PD-1 and Anti-CTLA-4 Therapy in Non-Small Cell Lung Cancer   (Now Available) (ID 2065)

      10:15 - 18:15  |  Presenting Author(s): Boris Sepesi

      • Abstract
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have induced durable responses in selected non-small cell lung cancer (NSCLC) patients. However, ICIs have also shown to induce tumor pseudo-progression in some cases. We report the incidence and consequences of a distinct phenomenon – the apparent radiographic progression of lymph nodes without pathological evidence of tumor – that we define “nodal immune flare” (NIF), following neoadjuvant ICIs in the NEOSTAR phase 2 trial of nivolumab or nivolumab plus ipilimumab for operable NSCLCs.

      Method

      NEOSTAR randomized 44 patients with stage I-IIIA (AJCC 7th edition) to nivolumab (3 mg/kg IV, days 1, 15, 29) or nivolumab/ipilimumab (1 mg/kg IV, day 1) with planned surgery between 3-6 weeks after last dose. Computed tomography (CT) and positron emission tomography (PET-CT) were obtained prior to ICIs and prior to resection. Response Evaluation Criteria in Solid Tumors v1.1 were used to evaluate responses.

      Result

      44 patients, median age 66 years (range 43-83), 28 (64%) males, 37 (84%) white were randomized to nivolumab (n=23) or nivolumab/ipilimumab (n=21). 26 (59%) had adenocarcinoma, 17 (39%) squamous cell, 1 (2%) adenosquamous carcinoma. 23 (52%) stage I, 12 (27%) stage II, 9 (20%) stage IIIA. 39 (89%) underwent complete resection, 2 off trial, and 5 (11%) were not resected.

      NIF occurred in 5/44 (11%) patients, 3 post nivolumab (3/23, 13%) and 2 (2/21, 10%) post nivolumab/ipilimumab. All patients had no evidence of malignancy in nodes of interest prior to ICIs. 2 (2/26, 8%) occurred in adenocarcinoma and 3 (3/17, 18%) in squamous cell. 2 (5%) required additional invasive restaging, 3 (7%) change in surgical plan, 1 (2%) declined surgery, 1 (2%) was thought to have disease progression and was treated with chemotherapy plus ICI prior to resection off study, and 1 (2%) underwent planned resection. Pathologic evaluation of the flared nodes revealed no evidence of cancer in all 5 patients, rather demonstrated noncaseating granulomata.

      In a previous neoadjuvant trial utilizing platinum-based chemotherapy with nintedanib, we did not observe NIF in 21 patients in absence of pathologic evidence of tumor progression (primary or nodal metastases).

      Conclusion

      NIF occurred in 11% of patients following neoadjuvant ICIs and changed treatment plan in 9% of patients. This is the first preliminary report of NIF in operable NSCLCs treated with neoadjuvant single and combined ICIs. Considering the number of ongoing neoadjuvant immunotherapy trials, we highlight the importance of judicious and invasive restaging of sites of suspected progression after neoadjuvant ICIs prior to definitive treatment decisions.

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