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BackgroundA majority of patients with advanced NSCLC develop disease progression with first-line immune-checkpoint inhibitors (ICI) ± chemotherapy. In the setting of ICI resistance, effective strategies to provide deep and durable responses are urgently needed. Lifileucel (LN-144) and LN-145 are centrally manufactured (cryopreserved drug-product, 22-day manufacturing process) autologous TIL products that have demonstrated activity in advanced melanoma, cervical cancer, and head and neck carcinoma.1–4 Here, we report the first safety and efficacy data for LN-145 as monotherapy in patients with advanced NSCLC.MethodsIOV-COM-202 (NCT03645928) is a phase 2 multicenter, multicohort, open-label study evaluating autologous TIL cell therapy in patients with solid tumors. We report data from Cohort 3B, investigating LN-145 monotherapy in patients with advanced or metastatic NSCLC. Eligibility required 1–3 prior lines of systemic therapy, including either ICI or oncogene-directed therapy. Treatment included nonmyeloablative lymphodepletion, TIL infusion, and ≤6 interleukin-2 doses. Primary endpoints were safety (incidence of Grade ≥3 treatment-emergent adverse events [TEAEs]) and objective response rate (ORR, investigator-assessed using RECIST v1.1). Exploratory biomarker analyses, including T-cell receptor (TCR) repertoire, were performed.ResultsAs of 24June2021, 28 patients received LN-145 (full-analysis set [FAS]; table 1) and 24 were efficacy-evaluable; all had received prior ICI. TIL were most commonly harvested from lung metastases (57.1%). Safety was consistent with the underlying disease and known TEAE profiles of nonmyeloablative lymphodepletion and interleukin-2. Grade ≥3 TEAEs in ≥30% of patients were thrombocytopenia and anemia. The ORR in the FAS and efficacy-evaluable set was 21.4% (6/28) and 25.0% (6/24; figure 1), respectively. Median duration of response was not reached and 83% (5/6) of responses were ongoing at last follow-up (median study follow-up, 8.2 months). One patient had a complete metabolic response, ongoing at 20.7 months; 2 responses occurred in patients who were PD-L1–negative. All responders received ≥2 prior lines of systemic therapy. Twenty-six patients had TIL available from the final drug-product for TCR repertoire analysis; mean (min-max) number of unique TCR clones was 13,142 (3093–35,734) and Shannon Entropy index was 7.34 (3.7–12). Updated data will be presented.Abstract 458 Figure 1Best percentage change from baseline in target lesion sum of diameters for efficacy-evaluable setAbstract 458 Table 1Baseline patient demographic and clinical characteristics; efficacy parametersConclusionsLN-145 was successfully manufactured and one-time treatment produced an expected safety profile and durable responses in heavily pretreated patients with NSCLC, regardless of PD-L1 expression. The activity of LN-145 monotherapy is encouraging and warrants further investigation of LN-145 as a single-agent and in combination in patients with NSCLC in ongoing studies IOV-LUN-202 (NCT04614103) and IOV-COM-202 Cohorts 3A and 3C (3B closed to enrollment).AcknowledgementsThis study and analysis were funded by Iovance Biotherapeutics, Inc. (San Carlos, CA, USA). Writing support was provided by Amanda Kelly (Iovance); graphics support was provided by Cognition Studio (Seattle, WA, USA).Trial RegistrationNCT03645928ReferencesSarnaik AA, et al. J Clin Oncol 2021; doi: 10.1200/JCO.21.00612.. Thomas SS, et al. J Clin Oncol 2021;39: (suppl; abstract 9537).Jazaeri A, et al. J Clin Oncol 2019;37: (suppl; abstract 2538).Jimeno A, et al. J Immunother Cancer 2020;8: (suppl; abstract A378).Ethics ApprovalThe study was approved by Advarra Institutional Review Board, approval number Pro00035064 and all study participants provided written consent via signature of the IRB-approved Informed Consent form.

Background Single agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored. Methods IOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naive HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG Results Nine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached. Conclusions LN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented. Trial Registration NCT03645928 Ethics Approval The study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

Background TIL (especially CD8+ T cells) in the tumor microenvironment is associated with survival outcomes in many solid tumors, including melanoma (Mel), head and neck squamous cell carcinoma (HNSCC), and non-small cell lung cancer (NSCLC). Lifileucel (LN-144), has shown efficacy with durable responses in advanced melanoma (Mel) (Sarnaik et al., ASCO 2020), metastatic cervical cancer (Jazaeri et al., ASCO 2019), and LN-145 + pembrolizumab in HNSCC (Jimeno et al., SITC 2020). TIL therapy has shown evidence of efficacy in metastatic NSCLC in a Phase 1 study (Creelan et al., ASCO 2020). Methods IOV-COM-202 (NCT03645928) is a Phase 2 global, open-label multi-cohort, non-randomized study designed to evaluate the safety and efficacy of TIL therapy as a single agent or in combination with immune checkpoint inhibitors. All patients receive either, lifileucel, LN-145 or LN-145-S1 (PD-1 select TIL), which is manufactured at centralized GMP facilities generating a cryopreserved infusion product which is shipped to the treatment centers. Cohort 1, 2 and 3 enroll Mel, HNSCC and NSCLC patients, respectively (Table 1). Patients undergo a nonmyeloablative lymphodepletion (NMA-LD) regimen prior to TIL infusion, followed by up to 6 doses of intravenous IL-2. Patients in Cohorts 1A, 2A, and 3A start pembrolizumab following tumor harvest for TIL generation, but prior to NMA-LD. Pembrolizumab is dosed per label. Patients in Cohorts 1B, IC and 3B receive LN-145-S1, lifileucel, and LN-145, respectively. Cohort 3C patients receive a dose of ipilimumab and nivolumab prior to tumor harvest, with nivolumab continuing Q4W for up to 2 years, or until progression or unacceptable toxicity. Key eligibility includes: ≥ 18 years of age; RECIST measurable disease; ≥ 1 lesion(s) available for TIL generation; ECOG PS 0-1. The primary endpoint: ORR per RECIST v1.1. Secondary endpoints: safety, CR rate, DOR, DCR, PFS, and OS. Table 1.IOV-COM-202 Study DesignCohortTIL ManufacturingCohort 1A: Melanoma PD-1/ PD-L1 Naïve LN-144 + Pembrolizumab N=12LN-144: 22-day manufacturingCohort 1B: Melanoma ≥1 prior systemic therapies LN-145-S1 N up to 27LN-145-S1: PD-1 selected TILCohort 1C: Melanoma ≥1 prior systemic therapies LN-144 Gen 3 N up to 27LN-144 Gen 3: 16-day manufacturingCohort 2A: Head and Neck PD-1/ PD-L1 Naïve LN-145 + Pembrolizumab N=19LN-145: 22-day manufacturingCohort 3A: NSCLC PD-1/ PD-L1 Naïve LN-145 + Pembrolizumab N=12LN-145: 22-day manufacturingCohort 3B: NSCLC ≥1 prior systemic therapies LN-145 N=12LN-145: 22-day manufacturingCohort 3C: NSCLC 1 prior systemic therapy TIL + Ipilimumab / Nivolumab N up to 26 Citation Format: Scott Gettinger, Harriet Kluger, Adam Schoenfeld, Allison Betof-Warner, Kai He, Ammar Sukari, Bernard Doger de Speville Uribe, Sylvia Lee, Simon Haefliger, Zelanna Goldberg, Alex Cacovean, Rana Fiaz, Guang Chen, Madan Jagasia, Friedrich Graf Finckenstein, Maria Fardis, Antonio Jimeno. A Phase 2, multicenter study of autologous tumor infiltrating lymphocytes (TIL, LN 144/LN-145/LN-145-S1) in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT235.

Objective To investigate whether anterior choroidal artery (AChA) territory sparing or AChA infarction restricted to the medial temporal lobe (MT), implying good collateral status, predicts good outcome, defined as modified Rankin Scale 0–2, at discharge in acute internal carotid artery (ICA) occlusion. Methods The authors studied consecutive patients with acute ICA occlusion admitted to an academic medical centre between January 2002 and August 2010, who underwent MRI followed by conventional angiography. The pattern of AChA involvement on initial diffusion-weighted imaging was dichotomised as spared or MT only versus other partial or full. The association of AChA infarct patterns and good outcome at discharge was calculated by multivariate logistic regression with adjustment. Results For the 60 patients meeting entry criteria, mean age was 68.3 years and median admission NIH Stroke Scale score was 19. AChA territory was spared or restricted to the MT in 27 patients and other partially involved or fully involved in 33 patients. AChA territory spared or ischaemia restricted to MT only, compared with other partial infarct patterns or full infarct, was independently associated with good discharge outcome (44.4% vs 12.1%, OR 7.24, 95% CI 1.32 to 39.89, p=0.023). Conclusion In acute ICA occlusion, the absence of AChA infarction or restriction to the MT is an independent predictor of good discharge outcome. Analysis of AChA infarct patterns may improve early prognostication and decision-making.

Background and Purpose— The purpose of this study was to evaluate the potential clinical value of arterial spin-labeled (ASL) perfusion MRI in acute ischemic stroke (AIS) through comparison with dynamic susceptibility contrast (DSC) enhanced perfusion MRI. Methods— Pseudocontinuous ASL with 3-dimensional background-suppressed gradient and spin echo readout was applied with DSC perfusion MRI on 26 patients with AIS. ASL cerebral blood flow and multiparametric DSC perfusion maps were rated for image quality and lesion severity/conspicuity. Mean ASL cerebral blood flow and DSC perfusion values were obtained in main vascular territories. Kendall coefficient of concordance was calculated to evaluate the reliability of ratings. Spearman correlation coefficients were calculated to compare ratings and quantitative perfusion values between ASL and DSC perfusion maps. Results— ASL cerebral blood flow and DSC perfusion maps provided largely consistent results in delineating hypoperfused brain regions in AIS. Hyperemic lesions, which also appeared frequently in the AIS cases studied, were more conspicuous on ASL cerebral blood flow than on DSC cerebral blood flow, mean transit time and time to the maximum of the tissue residual function maps. Conclusions— As a rapid, noninvasive, and quantitative technique, ASL has clinical use in detecting blood flow abnormalities in patients with AIS.