An ex vivo Platform to Guide Drug Combination Treatment in Relapsed/Refractory Lymphoma (Sci Transl Med, Oct 2022)

/ 2022, Latest Happenings, Research / By

Jasmine Goh 1, Sanjay De Mel 2 3, Michal M Hoppe 1, Masturah Bte Mohd Abdul Rashid 4, Xi Yun Zhang 1, Patrick Jaynes 1, Esther Ka Yan Ng 1, Nur’Atiqa Diana Binti Rahmat 1, Jayalakshmi 1, Clementine Xin Liu 3, Limei Poon 2 3, Esther Chan 2 3, Joanne Lee 2 3, Yen Lin Chee 2 3, Liang Piu Koh 3, Lip Kun Tan 5, Teck Guan Soh 5, Yi Ching Yuen 6, Hoi-Yin Loi 7, Siok-Bian Ng 1 2 8, Xueying Goh 9, Donovan Eu 9, Stanley Loh 7, Sheldon Ng 7, Daryl Tan 10 11, Daryl Ming Zhe Cheah 12, Wan Lu Pang 12, Dachuan Huang 12, Shin Yeu Ong 11, Chandramouli Nagarajan 11, Jason Yongsheng Chan 13 14, Jeslin Chian Hung Ha 13, Lay Poh Khoo 13, Nagavalli Somasundaram 13, Tiffany Tang 13, Choon Kiat Ong 12 15 16, Wee-Joo Chng 1 2 3 17, Soon Thye Lim 13 14 18, Edward K Chow 1 2 19 20 21, Anand D Jeyasekharan 1 2 3 17

Affiliations

  • 1Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
  • 2NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University Singapore, Singapore 117599, Singapore.
  • 3Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore 119074, Singapore.
  • 4KYAN Therapeutics, Singapore 118258, Singapore.
  • 5Department of Laboratory Medicine, National University Hospital, Singapore 119074, Singapore.
  • 6Department of Pharmacy, National University Health System, Singapore 119074, Singapore.
  • 7Department of Diagnostic Imaging, National University Hospital, Singapore 119074, Singapore.
  • 8Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
  • 9Department of Otolaryngology, National University Hospital, Singapore 119074, Singapore.
  • 10Mount Elizabeth Novena Hospital, Singapore 329563, Singapore.
  • 11Department of Haematology, Singapore General Hospital, Singapore 169608, Singapore.
  • 12Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 169610, Singapore.
  • 13Division of Medical Oncology, National Cancer Centre Singapore, Singapore 169610, Singapore.
  • 14SingHealth Duke-NUS Blood Cancer Centre, Singapore 168582, Singapore.
  • 15Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore 169857, Singapore.
  • 16Genome Institute of Singapore, A*STAR, Singapore 138672, Singapore.
  • 17Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
  • 18Office of Education, Duke-NUS Medical School, Singapore 169857, Singapore.
  • 19Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
  • 20N.1 Institute for Health, National University of Singapore, Singapore 117456, Singapore.
  • 21Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.

Abstract

Although combination therapy is the standard of care for relapsed/refractory non-Hodgkin’s lymphoma (RR-NHL), combination treatment chosen for an individual patient is empirical, and response rates remain poor in individuals with chemotherapy-resistant disease. Here, we evaluate an experimental-analytic method, quadratic phenotypic optimization platform (QPOP), for prediction of patient-specific drug combination efficacy from a limited quantity of biopsied tumor samples. In this prospective study, we enrolled 71 patients with RR-NHL (39 B cell NHL and 32 NK/T cell NHL) with a median of two prior lines of treatment, at two academic hospitals in Singapore from November 2017 to August 2021. Fresh biopsies underwent ex vivo testing using a panel of 12 drugs with known efficacy against NHL to identify effective single and combination treatments. Individualized QPOP reports were generated for 67 of 75 patient samples, with a median turnaround time of 6 days from sample collection to report generation. Doublet drug combinations containing copanlisib or romidepsin were most effective against B cell NHL and NK/T cell NHL samples, respectively. Off-label QPOP-guided therapy offered at physician discretion in the absence of standard options (n = 17) resulted in five complete responses. Among patients with more than two prior lines of therapy, the rates of progressive disease were lower with QPOP-guided treatments than with conventional chemotherapy. Overall, this study shows that the identification of patient-specific drug combinations through ex vivo analysis was achievable for RR-NHL in a clinically applicable time frame. These data provide the basis for a prospective clinical trial evaluating ex vivo-guided combination therapy in RR-NHL.

PMID: 36260690  DOI: 10.1126/scitranslmed.abn7824

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