denotes an abstract that is clinically relevant.
denotes that this is a recommended PHD Trainee Session.
denotes that this is a ticketed session.Program: Oral and Poster Abstracts
Session: 624. Lymphoma: Therapy with Biologic Agents, excluding Pre-Clinical Models: Poster II
Introduction: A single institution study conducted at the National Cancer Institute (NCI) using anti-CD19 CAR T cells with CD28 and CD3-zeta signaling domains showed durable remissions in subjects with relapsed/refractory advanced B-cell malignancies (Kochenderfer et al. Blood 2012, JCO 2014, ASH 2014). In the NCI study, anti-CD19 CAR T cells expanded within 1 week of administration and generally cleared the peripheral blood within 2 months. Anti-CD19 CAR T cell infusion resulted in rapid elevation and subsequent resolution of circulating cytokines and chemokines within 3 weeks (Bot et al. ASCO 2015). KTE-C19 utilizes the same anti-CD19 CAR construct investigated at the NCI, manufactured using an optimized 6-8 day process (Better et al. ASCO 2014). Preliminary characterization of KTE-C19 expansion and serum pharmacodynamic (PD) markers from ZUMA-1 are presented.
Methods: Subjects received KTE-C19 at a target dose of 2 x 106 (1 x 106 minimum) CAR-positive T cells/kg body weight after undergoing a fixed dose conditioning chemotherapy regimen of cyclophosphamide and fludarabine. KTE-C19 was characterized pre- and post-infusion by multiparameter flow cytometry for CAR expression and major phenotypic markers. KTE-C19 expansion and clearance was also monitored by multiparameter flow cytometry and quantitative PCR (qPCR) at weeks 1, 2, 4 and months 3 and 6 respectively. Forty one analytes from serum samples were evaluated by EMD Millipore Luminex® xMAP® multiplex assays at Days -5 (prior to conditioning chemotherapy), 0, 1, 3, 5, 7, 14 and 28 for a broad panel of cytokines, chemokines and immune effector related markers. Maximum fold increase (MFI) was defined as the maximum fold change of measured analytes above baseline (Day -5). Time to maximum value and time to resolution were calculated among subjects with increases after commencement of conditioning chemotherapy. Comparisons of fold increase were not adjusted for multiplicity.
Results: As of 28 July 2015, 6 subjects have received KTE-C19. Three subjects had post-infusion samples evaluable for CAR T-cell expansion by qPCR. Peak levels occurred within 7 days and KTE-C19 was detectable at 1 month. Additional qPCR monitoring is ongoing. Circulating cytokines, chemokines and immune effector markers have been evaluated in 4 subjects. Samples post conditioning and pre-KTE-C19 infusion showed significant increases in the levels of IL-15 (p<0.005) and MCP-1 (p<0.030). Cytokine and chemokine levels achieved their peak levels 1-10 days post KTE-C19 infusion and returned to baseline generally within 3 weeks. Key pro-inflammatory markers were substantially upregulated as indicated in the table. Additional monitoring of KTE-C19 persistence (by qPCR), phenotype and activation status of CAR T cells is ongoing. Updated results will be presented. Pre-infusion characterization of KTE-C19 with respect to CAR expression and T-cell subsets including CD4, CD8, naïve, central memory and effector memory are presented in a separate ASH abstract.
Conclusion: Six subjects with refractory aggressive NHL have received KTE-C19. CAR T cells expanded substantially and persisted through at least 1 month in 3 subjects evaluated to date. Pro-inflammatory, immune-homeostatic cytokines and chemokines peaked within 2 weeks. Timing of peak KTE-C19 expansion and serum cytokine profiles and clearance in this multicenter study with an optimized, shortened manufacturing process were consistent with results of the NCI study. This first biomarker analysis of ZUMA-1 demonstrates the PD activity of KTE-C19 and will help optimize future CAR T cell therapy. Clinical trial: NCT02348216.
|
MFI (range) |
Time to Maximum Median Days (range) |
Time to Resolutiona Median Days (range) |
IL-6 |
141 (17, 1010) |
5 (3, 9) |
18.5 (9, 28) |
IFN-gamma |
167 (8, 4387) |
4 (3, 5) |
9 (7, 10) |
CRP |
27 (1, 57) |
5 (3, 5) |
7 (7, 13) |
IL-15 |
22 (12, 55) |
2 (1, 7) |
9 (9, 9) |
IL-2 |
7 (1, 31) |
1 (1, 3) |
5 (3, 5) |
IL-10 |
132 (3, 561) |
5 (5, 5) |
9 (7, 11) |
MCP-1 |
16 (2, 25) |
2 (1, 5) |
7 (3, 10) |
Granzyme B |
42 (27, 773) |
5 (5, 7) |
8.5 (7, 14) |
a Time to resolution is the first post-KTE-C19 infusion day at which the level was ≤ 2x baseline.
Disclosures: Rossi: Kite Pharma: Employment , Equity Ownership ; Amgen: Equity Ownership . Off Label Use: Tocilizumab for the management of CRS . Go: Kite Pharma: Employment , Equity Ownership ; Amgen: Equity Ownership . Shen: Kite Pharma: Employment , Equity Ownership . Sherman: Amgen: Equity Ownership ; Kite Pharma: Employment , Equity Ownership . Locke: Kite Pharma: Other: Scientific Advisory Boards . Bartlett: Insight: Research Funding ; Janssen: Research Funding ; Kite: Research Funding ; Medimmune: Research Funding ; Genentech: Research Funding ; Pharmacyclics: Research Funding ; Colgene: Research Funding ; Millennium: Research Funding ; Novartis: Research Funding ; Pfizer: Research Funding ; Gilead: Consultancy , Research Funding ; Seattle Genetics: Consultancy , Research Funding ; MERC: Research Funding ; Dynavax: Research Funding ; Idera: Research Funding ; Portola: Research Funding ; Bristol Meyers Squibb: Research Funding ; Infinity: Research Funding ; LAM Theapeutics: Research Funding . Siddiqi: Pharmacyclics/Jannsen: Speakers Bureau ; Seattle Genetics: Speakers Bureau ; Kite pharma: Other: attended advisory board meeting . Navale: Amgen: Equity Ownership ; Kite Pharma: Employment , Equity Ownership . Elias: Kite Pharma: Employment , Equity Ownership ; Amgen: Equity Ownership . Wiezorek: Kite Pharma: Employment , Equity Ownership , Other: Officer of Kite Pharma . Bot: Kite Pharma: Employment , Equity Ownership .
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