TY - JOUR
T1 - Assessing CAR T-Cell Therapy Response Using Genome-Wide Sequencing of Cell-Free DNA in Patients With B-Cell Lymphomas
AU - Goodman, Aaron M.
AU - Holden, Kimberly A.
AU - Jeong, Ah Reum
AU - Kim, Lisa
AU - Fitzgerald, Kerry D.
AU - Almasri, Eyad
AU - McLennan, Graham
AU - Eisenberg, Marcia
AU - Jahromi, Amin H.
AU - Hoh, Carl
AU - Hurley, Michael
AU - Mulroney, Carolyn
AU - Tzachanis, Dimitrios
AU - Ball, Edward D.
AU - Jensen, Taylor J.
AU - Kurzrock, Razelle
N1 - Funding Information:
The authors thank Doctor Bob and The Shillman Foundation for their grant, which made this work possible.
Funding Information:
The authors thank Doctor Bob and The Shillman Foundation for their grant, which made this work possible. Financial disclosure: Supported by the Joan and Irwin Jacobs Fund, and by the National Cancer Institute grant P30 CA023100 (RK) and by Laboratory Corporation of America (Labcorp). A.H.J. is supported by the NIH T32-4T32EB005970 grant. Parts of the data analyses were funded by Labcorp. Conflict of interest statement: A.M.G. receives speaking and consulting fees from Seattle Genetics and consulting fees from EUSA Pharma. K.A.H. K.D.F. E.A. G.M. M.E. and T.J.J. are employees of Laboratory Corporation of America (Labcorp). T.J.J. is an advisor to PetDx. R.K. receives research funding from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, Medimmune, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant, as well as consultant and/or speaker fees and/or advisory board for X-Biotech, Neomed, Pfizer, Actuate Therapeutics, Roche, Turning Point Therapeutics, TD2/Volastra, Bicara Therapeutics, Inc. has an equity interest in IDbyDNA and CureMatch Inc, serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. Authorship statement: A.M.G. conceptualized and implemented the research, collected the data, and provided critical review of the manuscript. K.A.H. L.K. K.D.F. E.A. G.M. M.E. A.H.J. C.H. M.H. C.M. D.T. E.D.B. contributed to data acquisition and provided critical review of the manuscript. A.J. collected and analyzed the data and wrote the original draft of the manuscript. T.J.J. analyzed the data and wrote the original draft of the manuscript. R.K. acquired funding, supervised the research, and provided critical review of the manuscript. All authors approve of the final manuscript. Financial disclosure: See Acknowledgments on page XXXX.
Funding Information:
Financial disclosure: Supported by the Joan and Irwin Jacobs Fund, and by the National Cancer Institute grant P30 CA023100 (RK) and by Laboratory Corporation of America (Labcorp). A.H.J. is supported by the NIH T32-4T32EB005970 grant. Parts of the data analyses were funded by Labcorp.
Publisher Copyright:
© 2021 The American Society for Transplantation and Cellular Therapy
PY - 2021
Y1 - 2021
N2 - Methods that enable monitoring of therapeutic efficacy of autologous chimeric antigen receptor (CAR) T-cell therapy will be clinically useful. The aim of this study is to demonstrate the feasibility of blood-derived cell-free DNA (cfDNA) to predict CAR T-cell therapy response in patients with refractory B-cell lymphomas. Whole blood was collected before and throughout CAR T-cell therapy until day 154. Low-coverage (∼0.4×), genome-wide cfDNA sequencing, similar to that established for noninvasive prenatal testing, was performed. The genomic instability number (GIN) was used to quantify plasma copy number alteration level. Twelve patients were enrolled. Seven (58%) patients achieved a complete response (CR); 2 (25%), a partial response. Median progression-free survival was 99 days; median overall survival was not reached (median follow-up, 247 days). Altogether, 127 blood samples were analyzed (median, 10 samples/patient [range 8-13]). All 5 patients who remained in CR at the time of last measurement had GIN <170 (threshold). Two patients who attained CR, but later relapsed, and all but one patient who had best response other than CR had last GIN measurement of >170. In 5 of 6 patients with relapsed or progressive disease, increasing GIN was observed before the diagnosis by imaging. The abundance of CAR T-cell construct (absolute number of construct copies relative to the number of human genome equivalents) also showed a trend to correlate with outcome (day 10, P = .052). These data describe a proof-of-concept for the use of multiple liquid biopsy technologies to monitor therapeutic response in B-cell lymphoma patients receiving CAR T-cell therapy.
AB - Methods that enable monitoring of therapeutic efficacy of autologous chimeric antigen receptor (CAR) T-cell therapy will be clinically useful. The aim of this study is to demonstrate the feasibility of blood-derived cell-free DNA (cfDNA) to predict CAR T-cell therapy response in patients with refractory B-cell lymphomas. Whole blood was collected before and throughout CAR T-cell therapy until day 154. Low-coverage (∼0.4×), genome-wide cfDNA sequencing, similar to that established for noninvasive prenatal testing, was performed. The genomic instability number (GIN) was used to quantify plasma copy number alteration level. Twelve patients were enrolled. Seven (58%) patients achieved a complete response (CR); 2 (25%), a partial response. Median progression-free survival was 99 days; median overall survival was not reached (median follow-up, 247 days). Altogether, 127 blood samples were analyzed (median, 10 samples/patient [range 8-13]). All 5 patients who remained in CR at the time of last measurement had GIN <170 (threshold). Two patients who attained CR, but later relapsed, and all but one patient who had best response other than CR had last GIN measurement of >170. In 5 of 6 patients with relapsed or progressive disease, increasing GIN was observed before the diagnosis by imaging. The abundance of CAR T-cell construct (absolute number of construct copies relative to the number of human genome equivalents) also showed a trend to correlate with outcome (day 10, P = .052). These data describe a proof-of-concept for the use of multiple liquid biopsy technologies to monitor therapeutic response in B-cell lymphoma patients receiving CAR T-cell therapy.
KW - CAR T-cell therapy
KW - Cell-free DNA
KW - Cellular therapy
KW - Tumor marker
UR - http://www.scopus.com/inward/record.url?scp=85119147439&partnerID=8YFLogxK
U2 - 10.1016/j.jtct.2021.10.007
DO - 10.1016/j.jtct.2021.10.007
M3 - Article
C2 - 34655803
AN - SCOPUS:85119147439
SN - 2666-6367
JO - Transplantation and Cellular Therapy
JF - Transplantation and Cellular Therapy
ER -