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Now that's a SMARTrial: Ex Vivo Drug Screening in CLL as a Biomarker for Clinical Outcomes

Apr 29, 2021 1:00:00 PM / by Champions Oncology

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The current landscape for immunotherapy treatment of blood cancers has been advanced by breakthroughs in molecular diagnostics and personalized medicine. Now patients not only know the type of hematologic malignancy they have, but they may also be aware of unique mutations or variations associated with their cancer that can instruct treatment choices.

An observational trial called the Systematic and Mechanism-based Approach to Rational Treatment Trials of Blood Cancer (SMART) is currently underway and its primary objective is to use ex vivo drug sensitivity screening to determine which drugs may be most effective for the primary treatment of different hematologic malignancies[1]. Blood, bone marrow aspirate or lymph node tissue can be used for this screening against a large drug compound library within seven days of sample collection. This approach is considered to be potentially better at mapping drug sensitivity patterns for a patient’s cancer and may be superior to current biomarker-based approaches that were developed with small patient cohorts and limited drug libraries. This approach may also be more effective at linking genotype to phenotype in terms of the molecular basis of an individual’s tumor growth.

This study includes patients with a wide range of hematologic malignancies, including leukemia, lymphoma, or myeloma (ALL, AML, CLL, T-PLL, MCL, or MM) that are treatment naïve[2]. An042921_BlogInside-jpg interim analysis of this data has suggested this ex vivo screening protocol can provide clinically meaningful drug sensitivity information. The examination of in vivo responses classified as response (Resp), incomplete response (IResp) or progressive disease (PD) revealed that PD samples were significantly less responsive to all ex vivo drugs that were screened relative to Resp samples. Specific analysis of different drugs consistently worked better across all Resp samples whereas others did not show a consistent trend. This analysis has also uncovered previously unused chemotherapeutic drugs that were so effective ex vivo that that were used to treat an otherwise treatment-refractory patient.

These interim findings indicate that ex vivo screening approaches for drugs or biologics, including therapeutic antibodies or modified cell products (like CAR T cells), can be used to improve treatment selection. These screenings can be done within days of sample collection so they do not introduce undesirable treatment delays and can be used for both treatment naïve and relapsed/refractory patients. Further data analysis is needed to determine if this ex vivo drug sensitivity screening can be used to predict the time to next treatment. Ex vivo drug sensitivity screening is well suited to hematologic malignancies because there is no dependency on tumor tissue architecture in predicting penetration and efficacy of treatment.

Further studies are certain to improve the accuracy, reproducibility, and turnaround time of ex vivo drug sensitivity screening and such optimizations will likely require smaller sample volumes and will screen larger panels of drugs or biologics.

 

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[1] https://clinicaltrials.gov/ct2/show/study/NCT03488641

[2] Liebers, Nora, et al. "Ex-Vivo Drug Response Profiling for Tailoring Treatment in Hematologic Malignancies: The Prospective Non-Interventional SMART-Trial." (2019): 376-376.

Tags: Hematological Malignancies