444 Potential feasibility of core needle biopsy tumor tissue procurement method for TIL cell therapy with OBX-115 in non-small cell lung cancer (NSCLC)

<h3>Background</h3> Non-engineered tumor-infiltrating lymphocyte (TIL) cell therapy has demonstrated antitumor activity in metastatic NSCLC.^{1 2} Historically, surgical tumor tissue procurement has been required to manufacture TIL, but surgery is a barrier to treatment for many patients with NSCLC. TIL engineered with regulatable membrane-bound IL15 (cytoTIL15^TM cells) demonstrate IL2-independent expansion and preclinical functionality using multiple solid tumor types, including NSCLC^{3 4} and we hypothesized that the unique manufacturing process would require less tumor tissue to generate TIL without compromising product characteristics. Recently, OBX-115 was manufactured using core needle biopsy (CNB) tumor tissue with encouraging outcomes in patients with advanced melanoma.⁵ Herein, we compared the characteristics of NSCLC TIL manufactured from surgically resected tumor tissue vs. simulated CNBs (sCNBs). <h3>Methods</h3> Tumor tissue was collected in pairs from surgically resected tissue and sCNB performed on the same tumor post-excision. OBX-115 and non-engineered TIL were generated from tissues as described previously.⁶ TIL phenotype was evaluated using flow cytometry. Pairwise similarity of T-cell receptor (TCR) repertoires was assessed based on the top 100 clonotypes detected in each sample by TCR beta chain sequencing. TIL cytotoxicity was evaluated in 3D tumor-spheroid models generated from autologous patient-derived tumor cell lines (PDc). <h3>Results</h3> OBX-115 generated from four paired surgical and sCNB tissues showed similar IL2-independent expansion during rapid expansion protocol (REP). OBX-115 drug product from both surgical and sCNB tissues showed similar CD8+ T-cell enrichment (surgical, 95.4±2.6%; sCNB, 95.7±1.7%, p=0.70), similar TCR profiles (figure 1), and potent cytotoxicity against autologous PDc (figure 2). Compared with non-engineered TIL, OBX-115 from both surgical and sCNB tissues showed significantly lower expression of the exhaustion marker programmed cell death protein-1 (PD-1) (OBX-115 surgical, 7.13±3.34%; OBX-115 sCNB, 6.29±5.30%; non-engineered, 27.7±16.1%; p&lt;0.05, one-way ANOVA) and greater enrichment of a CD8+CD39-CD69- ‘stem-like’ progenitor cell phenotype (OBX-115 surgical, 61.13±10.88%; OBX-115 sCNB, 58.59±21.71%; non-engineered, 5.0±2.9%; p&lt;0.05, one-way ANOVA). <h3>Conclusions</h3> OBX-115 cells were successfully generated from NSCLC tumor tissue, with similar product characteristics between those from sCNB and surgical resection. OBX-115 cells were polyclonal, cytotoxic toward autologous PDc, and displayed a lower frequency of exhausted cells and higher proportion of ‘stem-like’ progenitor cells previously associated with clinical success of TIL cell therapy⁷ compared with non-engineered TIL. These results suggest the potential feasibility of a minimally invasive tumor tissue procurement method for TIL cell therapy manufacturing using CNB in patients with NSCLC, potentially expanding the eligible patient population. <h3>References</h3> Schoenfeld AJ, <i>et al</i>. Lifileucel, an autologous tumor-infiltrating lymphocyte monotherapy, in patients with advanced non-small cell lung cancer resistant to immune checkpoint inhibitors. <i>Cancer Discov</i> 2024. Creelan BC, <i>et al</i>. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. <i>Nat Med</i> 2021;<b>27</b>(8):1410–1418. Pedro, Kyle D, <i>et al</i>. ‘Abstract LB096: IL15-engineered tumor infiltrating lymphocytes (cytoTIL15TM) exhibit activity against autologous tumor cells from multiple solid tumor indications without IL2.’ <i>Cancer Research</i> 2023;<b>83</b>(8_Supplement):LB096-LB096. Ao Z, <i>et al</i>. ‘Abstract LB093: Engineering tumor infiltrating lymphocytes from sarcoma and colorectal tumors with membrane bound IL-15 for IL-2 independent expansion and enhanced cytotoxicity against autologous tumor cell lines.’ <i>Cancer Research</i> 2023;<b>83</b>(8_Supplement): LB093-LB093. Bernatchez C. ‘Minimally invasive tumor tissue procurement is feasible for clinical manufacturing of OBX-115 engineered tumor- infiltrating lymphocytes (TIL).’ <i>Cytotherapy</i> 2024 June;<b>26</b>(6):S154-S155. Burga R, <i>et al</i>. Abstract 348 ‘TIL engineered with membrane-bound IL15 (cytoTIL15™) are enriched for tumor-associated antigen reactivity and demonstrate pharmacologically tunable expansion and persistence in the presence of TAA.’ <i>J Immunother Cancer</i> 2023;<b>11</b>(348). Krishna S, <i>et al</i>. ‘Stem-like CD8 T cells mediate response of adoptive cell immunotherapy against human cancer.’ <i>Science</i> 2020;<b>370</b>(6522):1328–1334. <h3>Ethics Approval</h3> The study was approved by Memorial Sloan Kettering’s Ethics Board, protocol numbers 16-1566 and 12-245.