Dual-target natural killer cell engager for treatment of acute myeloid leukemia
7005. A first-in-human study of CD123 NK cell engager SAR443579 in relapsed or refractory acute myeloid leukemia, B-cell acute lymphoblastic leukemia, or high-risk myelodysplasia.
Anthony Selwyn Stein (City of Hope National Medical Center, Duarte, CA) presented preliminary safety and efficacy data from phase I/II trial of SAR443579 (SAR’579), a trifunctional natural killer (NK) cell engager for relapsed or refractory (r/r) acute myeloid leukemia (AML). SAR’579 targets CD123, which is widely expressed in hematologic malignancies, and co-engages NKp46 and Cd16a on NK cells, targeting NK cells to CD123-positive tumor cells. Prior preclinical studies indicate that SAR’579 depletes CD123-positive tumor cells ex vivo, and in non-human primates, SAR’579 is not associated with strong cytokine release or toxicity. Of the 23 patients with r/r AML participating in the study, 3 remain on treatment, 20 discontinued. No dose-limiting toxicities were observed in the dose escalation phase of the study. Grade 3 or 4 adverse events occurred in 18 patients (78.3%), and treatment-related adverse events occurred in 16 patients (69.6%). One case of grade 1 cytokine release syndrome occurred. Composite complete remission (cCR: complete response + complete response with incomplete platelet recovery) rate was 13.0% (3 of 23 patients). Median duration of response was not estimable, and median time to first CR was 16.1 weeks. Two of the responders remain in remission on treatment for 6.7 and 7.6 months, respectively. SAR’579 exhibits a manageable safety profile and promising clinical activity in highly pre-treated AML patients. The study is currently evaluating higher dose levels of SAR’579. SAR’579 was granted FDA Fast Track designation in May of 2023.
Characterization of tumor-infiltrating lymphocytes in young women with HR+/HER2- breast cancer and their associations with clinical outcomes
505. Association of tumor-infiltrating lymphocytes (TILs) with clinicopathologic characteristics and prognosis in young women with HR+/HER2- breast cancer (BC).
Megan E. Tesch (Dana-Farber Cancer Institute, Boston, MA - SITC Member) presented results of a study characterizing the extent and composition of tumor infiltrating lymphocytes (TILs) in hormone receptor positive (HR+) HER2 negative breast cancer in patients under 40 years and the impact of TIL subtypes on survival outcomes. High levels of TILs are associated with better clinical outcomes, especially in early-stage triple negative breast cancer (TNBC), but less is known about the tumor microenvironment (TME), TIL subtypes in the TME, and their impacts on patient prognosis and outcomes in HR+ disease. Tumor samples from a cohort of 390 patients diagnosed with Stage I – IIII HR+/HER2- breast cancer at age <= 40 years were analyzed, and TILs were assessed by multiplex immunofluorescence of patient tissue microarrays. Samples from patients of older age (36-40 years) were associated with high expression of CD8+ (cytotoxic) and PD1+ CD8+ (exhausted) TILs in stroma, and with higher levels of CD3+CD4+ (T helper) TILs in tumor compared to younger age groups (<36 years), suggesting a possible age-related change in immune cell composition. Samples from Black patients were associated with higher expression of stromal cytotoxic T cells, FOXP3+ CD3+ T cells (T regulatory cells; Tregs) and exhausted PD1+ TILs. No differences in intratumoral TIL composition were observed between races. High grade tumors were also associated with higher immune marker expression. High levels of intratumoral cytotoxic T cells were associated with improved overall survival (OS), high levels of T helper cells were associated with improved invasive breast cancer-free survival (iBCFS; intratumoral and stromal) and better rates of distant disease-free survival (DDFS; intratumoral). High levels of Tregs were associated with improved iBCFS (intratumoral and stromal) and DDFS (intratumoral). Increased levels of PD-1+ cells were associated with improved iBCFS (intratumoral and stromal), DDFS, (intratumoral and stromal), and OS (intratumoral). These results and further characterization of TILs and their interactions in the TME may contribute to the development of prognostic and predictive biomarkers in HR+/HER2- breast cancer, positively impacting treatment strategies, especially for younger patients.
Engineering safe and effective CAR T cells targeting CD47
2513. Targeting CD47 in lymphoid malignancies with CAR T cells.
Alexander Paul Boardman (Memorial Sloan Kettering Cancer Center, New York, NY) reported a preclinical study of CD47-targeting CAR T cells, a potential therapeutic strategy for malignancies that relapse due to CD19 antigen-loss escape. CD47, an anti-phagocytic “don’t eat me” receptor, is overexpressed in NHL. Two novel CD47 CAR cells were constructed. One expressed a single variable heavy chain nanobody (CD47-CAR), and the second expressed the CD47 binding domain of cognate receptor SIRP alpha (SIRPa-CAR). CD47-induced fratricide resulted in low levels of CD47-CAR T cell expansion, so CD47 on the CAR T cells was knocked out by CRISPR. CD47KO CD47 CAR T exhibited modest anti-tumor activity in mouse models. The lack of persistence and low cytotoxicity was due to CAR T cells sequestering in the thorax of the mice. SIRPa-CAR T cells were engineered to secrete the pro-inflammatory cytokine IL-18, which improved expansion and tumor clearance, but these cells caused high levels of toxicity in mice. To circumvent IL-18-induced toxicities, SIRPa Drug-OFF CAR in which a drug degrades the CAR in a proteosome-dependent manner was developed. SIRPa Drug-OFF CAR T cells exhibited reduced lung sequestration and improved anti-tumor cytotoxicity. These data indicate that CD47-targeting CAR T cells do have therapeutic potential, but CD47 CAR constructs need to be modified to achieve clinical effectiveness and safety.
For related research in CD47 and CAR T cell therapy, read this article from Beckett et al in JITC.
Association of loss-of-function variants of NOD2 with favorable response to checkpoint inhibition
2514. Association of common inherited NOD2 mutations with exceptional response to immune checkpoint inhibitors.
Megan Babette Barnet (Garvan Institute of Medical Research, Darlinghurst, NSW, Australia) presented a study of variations in an immune regulatory gene as a biomarker of improved anti-cancer immune response. Whole genome sequencing of a patient with an exceptional response (ExR) to targeted radiotherapy for metastatic melanoma, exhibiting a complete abscopal response, identified two loss-of-function variants of the NOD2 gene. NOD2 is an innate immune sensor, and functional NOD2 contributes to basal immune tolerance. A Nod2 null mouse model was generated. Nod2 null mice transplanted with a synergistic cell line showed a greater response to treatment with PD-1 blockade compared to wild-type litter mates, improved survival over 60 days, and tumors from NOD2 null mice had more CD8+ and CD4+ effector memory differentiated cells compared to NOD2 wild type mice. Genomes from individuals with ExR (PFS greater than 2 years, n=40) and non-responders (n=18) to anti-PD-(L)1 therapy for NSCLC were sequenced and compared to other lung cancer cohorts. 25% of ExR patients carried one or more NOD2 loss-of-function variants, more than twice the expected allele frequency. Gain of function NOD2 alleles were common in the cohort of non-responders and rare in the ExR cohort, and loss-of-function NOD2 alleles were identified in one-third of patients who achieved a complete response to PD-(L)1 therapy. These data support NOD2 as a potential biomarker for treatment stratification, and work to characterize the mechanism of action behind the exceptional responses is in progress.
ctDNA as a prognostic biomarker for lung patients receiving maintenance immunotherapy
2516. Association of ctDNA tumor fraction with survival in advanced non-small cell lung cancer (NSCLC) treated with maintenance durvalumab in the UNICANCER SAFIR02-Lung/IFCT1301 trial.
Filippo Gustavo Dall'Olio (Institut Gustave Roussy, Villejuif, France) presented an exploratory analysis of tumor fraction (TF) of circulating tumor DNA (ctDNA) as a biomarker for immune therapy, defined as the proportion of circulating ctDNA relative to circulating cell free DNA (cfDNA). Samples from the SAFIR02-Lung trial were analyzed. In this trial, patients received platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC). Patients who exhibited stable disease or response after four cycles of treatment were randomized to groups receiving durvalumab (Durvalumab) or standard of care (SOC) maintenance therapy. Results from this study indicated durvalumab prolonged survival only in the PD-L1 >= 1% subgroup. Plasma samples were taken after chemotherapy treatment, before randomization to Durvalumab or SOC. 50 out of 121 plasma samples from patients randomized to durvalumab were analyzed. Among patients with TF < 2%, progression free survival (PFS) was improved in the Durvalumab arm compared to the SOC arm (4.4 mos vs. 3.5 mos), as well as median overall survival (mOS; 25.5 mos vs 16.7 mos). This trend was not observed among patients with TF >= 3%. PFS was 1.4 mos for both groups, and mOS was 10.1 mos for Durvalumab, compared to 6 mos for SOC. In a multivariate model, TF was independently associated with worse PFS and OS. These data indicate that durvalumab maintenance therapy with immune checkpoint blockade likely will not benefit patient populations with high TF after chemotherapy and underscore the strong prognostic value of TF for future clinical trials.
For related research on ctDNA as a predictive biomarker for immunotherapy, read this article from Ricciuti et al in JITC.