376 | A PHASE 1, MULTICENTER, OPEN ‐ LABEL STUDY OF CC ‐ 99282 ALONE AND IN COMBINATION WITH RITUXIMAB IN PATIENTS WITH RELAPSED OR REFRACTORY NON ‐ HODGKIN LYMPHOMAS

Background: CC ‐ 99282 is a novel, oral cereblon (CRBN) E3 ligase modulator (CELMoD) agent that co ‐ opts CRBN to induce potent and targeted degradation of Ikaros and Aiolos, transcription factors that are known to be important for the normal differentiation and function of multiple types of hematopoietic cells. Non ‐ Hodgkin lymphomas (NHL) comprise diverse lymphoma subtypes with varying genomic alterations and clinical outcomes. Despite treatment advances, management of aggressive relapsed or refractory (R/R) NHL remains challenging. The ability of CC ‐ 99282 to spe-cifically target Ikaros and Aiolos for degradation provides a strong biological rationale for studying it for the treatment of patients with R/R B ‐ cell NHL, both as a single agent and in combination with rituximab, an approved humanized anti ‐ CD20 monoclonal multicenter, label, first in human study evaluating the safety, tolerability, and preliminary clinical activity alone and in combination with rituximab in patients with R/R B ‐ cell NHL. Methods: Eligible patients include those with R/R NHL, including diffuse large B ‐ cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma, or primary central nervous system lymphoma (PCNSL), who have relapsed on or are refractory to ≥ 2 lines of therapy (or who have received ≥ 1 prior line of standard therapy and are not eligible for any other therapy). This study is conducted in 2 parts: dose escalation (Part A) and dose expansion (Part B). Part A evaluates the safety and tolerability of escalating CC ‐ 99282 doses to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of CC ‐ 99282 monotherapy. In Part A, patients with R/R DLBCL or R/R FL receive oral CC ‐ 99282 once daily on intermittent schedules per 28 ‐ day cycle. Following the evaluation of the Bayesian logistic regression model recommendation as well as the safety and pharmacokinetic/pharmacodynamic data that are monitored continually, decisions on dose escalations are made by the safety review committee until the MTD/RP2D is reached. Part B will evaluate the safety and efficacy of CC ‐ 99282 administered at the RP2D alone or in combination with rituximab to confirm the RP2D of CC ‐ 99282. Treatment efficacy is assessed according to the Lugano Classification for NHL and the modified International PCNSL Collaborative Group criteria. Correlations between various biomarkers and clinical outcomes of treatment with CC ‐ 99282, alone or in combination with rituximab, will also be explored. Adverse events are monitored until 28 days following the final dose. Study treatments may be continued for up to 2 years, or until significant disease progression, unacceptable toxicity, or withdrawal. Background: Tabelecleucel (tab ‐ cel) is an investigational off ‐ the ‐ shelf, allogeneic Epstein ‐ Barr virus (EBV) ‐ specific T ‐ cell immunotherapy. Tab ‐ cel has shown clinical activity in patients with EBV + post ‐ transplant lymphoproliferative disease and other EBV ‐ associated diseases. We aim to comprehensively profile tab ‐ cel through high ‐ content immunophenotyping (IPT), T ‐ cell receptor (TCR) repertoire, cytokine polyfunctionality (PF), and differential gene expression patterns (GEP) using resting and EBV ‐ antigen stimulation states to model intrinsic effector responses associated with engagement of EBV + disease. Using this approach, we aim to identify corollaries associated with clinical outcomes. Methods: IPT was performed using targeted flow cytometry activation profiling (CD25/CD69), and 40 ‐ plex mass cytometry by time ‐ of ‐ flight (CyTOF). PF response and cytokine profiles were evaluated using the IsoLight single ‐ cell PF strength assay. TCR repertoires were assessed using TCR β immunoSEQ and GEP were evaluated using a custom Nanostring panel consisting of 333 T ‐ cell lineage gene targets. Results: Analyses for a subset of tab ‐ cel lots has been completed and are described here. This subset of tab ‐ cel lots varied in their CD4/CD8 composition, with the majority having proportionally higher CD8 + T cells ( > 70%). Baseline control expression of activation markers of 8.5 ± 2.1% increased to 65 ± 3.9% post ‐ activation with EBV + targets (Figure1A).BaselinecontrolPFwas0.58 ± 0.21%,anduponactivation tab ‐ cel demonstrated a 25.3 ‐ fold average induction of PF (Figure 1B). The resultant activated cytokine profiles are primarily comprised of effector and chemoattractive cytokines including IFN γ and MIP1 β . The tab ‐ cel manufacturing process effectively amplified and enriched for EBV ‐ specific TCRs that correspond back to a starting frequency of 0.52 ± 0.8% of the initial donor TCR repertoire (Figure 1C). Notably, cross comparison of tab ‐ cel enriched TCRs against publicly available databases (VDJdb, McPas ‐ TCR) identified previously curated EBV ‐ specific TCR β sequences as a component of the expanded repertoire. We are currently assessing the degree of convergence for TCR sequences against common antigen motifs across donors and corre-lationofIPTtopost ‐ activationPF.Analysis ofpost ‐ activation GEPand extended IPT by CyTOF are currently underway and will be reported at the time of presentation. Conclusions: The process for generating tab ‐ cel from unre-lated donors enriches for known EBV ‐ specific clones and results in a net amplification of EBV ‐ targeted T ‐ cell clonality. Upon activation, tab ‐ cel exhibits a multi ‐ factorial activation profile and demonstrates PF associated with secretion of effector and chemoattractive cytokines. Altogether this multi ‐ omics profiling will facilitate corollaries associated with clinical outcomes. EA – previously submitted to regional or national meetings (up to 1000 attendees) and EBMT 2021. The research was funded by: Atara Biotherapeutics to the abstract