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1640 Myeloid Derived Suppressor Cell Kinetics in Peripheral Blood Correlate with Efficacy and Toxicity of CAR T Cell Therapy in Relapsed or Refractory B Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 622. Lymphomas: Translational – Non-Genetic: Poster I
Hematology Disease Topics & Pathways:
Research, Biological therapies, adult, Translational Research, Lymphomas, B Cell lymphoma, Chimeric Antigen Receptor (CAR)-T Cell Therapies, Diseases, Therapies, immunology, Lymphoid Malignancies, Adverse Events, Biological Processes, Study Population, Human
Saturday, December 9, 2023, 5:30 PM-7:30 PM

David M Foureau, PhD1, Hamid Ehsan, MD, MBBS, MS, BS2, Fei Guo, PhD1*, Tahj Jones1*, Ryan W Jacobs, MD3, Bei Hu, MD4, Tamara K. Moyo, MD5*, Yifan Pang, MD6, Steven I. Park, MD7, Lawrence J. Druhan, PhD8, Ariel Bell, MPH9* and Nilanjan Ghosh, MD3

1Levine Cancer Institute, Atrium Health, Charlotte, NC
2Atrium health / Levine Cancer Institute, Waxhaw, NC
3Atrium Health Levine Cancer Institute, Charlotte, NC
4Department of Hematologic Oncology and Blood Disorders, Atrium Health / Levine Cancer Institute, Charlotte, NC
5Atrium Health / Levine Cancer Institute, Charlotte, NC
6Department of Hematologic Oncology and Blood Disorders, Atrium Health Levine Cancer Institute, Charlotte, NC
7Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC
8Hematology Oncology Translational Research Laboratory, Atrium Health Levine Cancer Institute, Charlotte, NC
9Atrium Health / Levine Cancer Institute, Charlotte

Introduction. CAR T-cell therapy is potentially curative for patients with relapsed or refractory B-cell lymphoma (BCL). However, about 60% of patients fail CAR T-cell therapy. Immune-related adverse events (irAE) like cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) occur in an inflammatory state. Myeloid-derived suppressor cells (MDSCs) expand during acute inflammation as steady-state hematopoiesis switches to emergency myelopoiesis. We hypothesized that the acute inflammatory conditions created by CAR T-cell therapy may alter MDSC kinetics and investigated MDSC expansion in the context of CAR T-cell efficacy and toxicity in BCL.

Methods. Patients with BCL receiving standard-of-care CAR T-cell therapy were enrolled in a prospective sample collection study. Blood samples were collected before lymphodepletion (baseline), prior to and at early intervals after CAR T-cell infusion. Viable white blood cell (WBC) and MDSC counts were evaluated by multicolor flow cytometry. Phenotypically, MDSCs were defined as immature myeloid cells (CD11b+ CD33+ HLA-DR-/low IL-4R+) and divided into monocytic (M-MDSC, CD14+) and polymorphonuclear (PMN-MDSC, CD15+) subsets. Clinical response was assessed by Lugano criteria at 1, 3 and 6 months. Incidence and severity of CRS and ICANS were recorded. Cell counts were analyzed by descriptive statistics and reported as mean ± standard error or fold-change from baseline. Kinetics of MDSCs in blood and correlation with clinical outcomes were evaluated by Wilcoxon matched pair signed rank t-test and Mann Whitney U-test.

Results. Forty-three BCL patients (41 large BCL, 2 mantle cell lymphoma) were enrolled in the study. Median age was 64 (range 27-83), 32.6% were female. Racial and ethnic minority groups represented 14% of enrolled subjects. One patient developed grade 5 ICANS and was not evaluable for response. Thirty-seven (86%) developed leukopenia and all received granulocyte colony stimulating factor (G-CSF) starting on day 5 post-CAR T infusion. WBC count fell sharply from baseline following lymphodepletion (7.7E+05±8.6E+04 baseline vs 2.9E+05±9.2E+04/mL, p<0.0001) and continued to decline 2-3 days post-CAR T infusion (baseline vs 1.4E+05±2.1E+04/mL, p<0.0001) before returning to baseline within 1 week post-CAR T (i.e. within 3 days of G-CSF). MDSCs followed similar kinetics early on but significantly increased from baseline levels by 1-week post-CAR T (3.4E+03±5.8E+02 baseline vs 8.5E+03±1.7E+02 /mL, p<0.0001). This effect was mainly driven by an exuberant expansion of M-MDSC observed in 33/43 patients (median 6.1-fold increase from baseline at 1 week, range 0.5-4301).

Seven patients (16.3%) had progressive disease (PD) at 1 month, 6 (13.9%) additional patients progressed at 3 months and 4 (9.3%) more progressed at 6 months after CAR T-cell infusion. M-MDSC expansion 1-week post-CAR T was only observed in 3/7 refractory patients compared with 28/35 responding patients (Fisher’s exact test, p=0.0635). Patients who progressed at 3 months had poorer M-MDSC retention compared to patients with sustained response (1.7E+02±6.1E+01 PD vs 1.4E+03±2.4E+01/mL at 2-week post-infusion, p<0.1). Similarly, patients who progressed at 6 months had lower M-MDSC compared with sustained responders (2.0E+02±8.1E+01 PD vs 4.5E+02±1.4E+02 ml at 1-month post-infusion, p<0.05).

Thirteen patients (30.2%) developed > grade 2 CRS and had lower PMN-MDSC retention rate 2-3 days post-CAR-T compared with those with no/low-grade CRS (4.4E+02±2.6E+02 vs 1.4E+03±3.9E+02/mL, p<0.05). Similarly, patients who had ICANS > grade 2 (n=14, 32.5%) had lower PMN-MDSC early retention compared to those with no or low-grade ICANS (5.0E+02±2.5E+02 vs 1.5E+03±4.1E+02/mL, p<0.05). Further analyses are currently underway to bridge these findings with the kinetics of CAR T-cells and T-cell repertoire post-CAR T.

Conclusions. The proinflammatory milieu after CAR-T and the use of G-CSF can lead to significant expansion of M-MDSCs. Rather than an impediment to CAR T therapy, M-MDSC expansion and retention are associated with favorable clinical response and PMN-MDSC with a lower risk of developing high grades CRS or ICANS. Whether MDSCs play a mechanistic role remains to be elucidated, but they may have a role as a biomarker in predicting outcomes after CAR T-cell therapy in BCL.

Disclosures: Foureau: Astrazeneca: Research Funding. Jacobs: AbbVie: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Teneobio: Research Funding; Genentech: Consultancy; SecuraBio: Consultancy, Speakers Bureau; Adaptive: Consultancy; Beigene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; AstraZeneca: Research Funding, Speakers Bureau; LOXO Oncology: Research Funding. Moyo: Kite Pharmaceuticals: Consultancy. Park: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Seattle Genetics: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. Ghosh: Roche NHL soultions panel: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Genentech/Roche, Bristol Myers Squibb,Gilead, Morphosys, AbbVie, Pharmacyclics,: Research Funding; see consulting and speaker's bureau.: Honoraria, Other: see consulting and speaker's bureau. ; AstraZenca, Janssen, Pharmacyclics, Kite pharma, BMS, Epizyme: Speakers Bureau; Seagen, TG Therapeutics, AstraZeneca, Phamacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, Kite Pharma, Beigene, Incyte, Lava Therapeutics, Incyte, Roche/Genentech Novartis, Loxo Oncology, AbbVie, enmab, Adaptive Biotech, ADC Therapeutics: Consultancy.

*signifies non-member of ASH