An <i>Ex Vivo</i> Platform for the Prediction of Clinical Response in Multiple Myeloma

Silva, Ariosto S.; Silva, Maria D; Sudalagunta, Praneeth Reddy; Distler, Allison; Jacobson, Timothy; Collins, Aunshka; Nguyen, Tuan; Song, Jinming; Chen, Dung-Tsa; Chen, Lu; Cubitt, Christopher L.; Baz, Rachid; Perez, Lia; Rebatchouk, Dmitri; Dalton, William S.; Greene, James M.; Gatenby, Robert A.; Gillies, Robert J.; Sontag, Eduardo D.; Meads, Mark B.; Shain, Kenneth H.

doi:10.1158/0008-5472.can-17-0502

Cited by 59 publications

(76 citation statements)

References 51 publications

(56 reference statements)

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“…Various three-dimensional cell culture methods, stromal coculture approaches, and advanced acquisition techniques to profile MM drug sensitivity have been reported. [11][12][13][14] However, these MM drug sensitivity profiling approaches have used CD138-selected MM cell cultures in the absence of other immune effector cells. Notably, in the preclinical development of Dara, unselected mononuclear cell (MNC) cultures were used to measure antibody-dependent cellular cytotoxicity (ADCC).…”

Section: Introductionmentioning

confidence: 99%

Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression

Walker¹,

VanWyngarden²,

Stevens³

et al. 2020

Blood Advances

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The oncogenic drivers and progression factors in multiple myeloma (MM) are heterogeneous and difficult to target therapeutically. Many different MM drugs have emerged, however, that attack various phenotypic aspects of malignant plasma cells. These drugs are administered in numerous, seemingly interchangeable combinations. Although the availability of many treatment options is useful, no clinical test capable of optimizing and sequencing the treatment regimens for an individual patient is currently available. To overcome this problem, we developed a functional ex vivo approach to measure patients’ inherent and acquired drug resistance. This method, which we termed myeloma drug sensitivity testing (My-DST), uses unselected bone marrow mononuclear cells with a panel of drugs in clinical use, followed by flow cytometry to measure myeloma-specific cytotoxicity. We found that using whole bone marrow cultures helped preserve primary MM cell viability. My-DST was used to profile 55 primary samples at diagnosis or at relapse. Sensitivity or resistance to each drug was determined from the change in MM viability relative to untreated control samples. My-DST identified progressive loss of sensitivity to immunomodulatory drugs, proteasome inhibitors, and daratumumab through the disease course, mirroring the clinical development of resistance. Prospectively, patients’ ex vivo drug sensitivity to the drugs subsequently received was sensitive and specific for clinical response. In addition, treatment with <2 drugs identified as sensitive by My-DST led to inferior depth and duration of clinical response. In summary, ex vivo drug sensitivity is prognostically impactful and, with further validation, may facilitate more personalized and effective therapeutic regimens.

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Section: Introductionmentioning

confidence: 99%

Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression

Walker¹,

VanWyngarden²,

Stevens³

et al. 2020

Blood Advances

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“…Responses to the currently employed combination therapies occur in the majority of patients initially and become less frequent as the disease relapses and acquires resistance to chemotherapeutic agents . Understanding the mechanisms of immune response and resistance to immunotherapeutic approaches are of considerable interest in multiple myeloma but few predictive biomarkers have been discovered and none of them have changed clinical practice so far …”

Section: Introductionmentioning

confidence: 99%

Peripheral blood biomarkers of early immune reconstitution in newly diagnosed multiple myeloma

et al. 2018

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Peripheral blood biomarkers of tumor microenvironment and immune surveillance are independent prognostic factors in multiple myeloma. The timing and prognostic impact of immune reconstitution has been studied after autologous hematopoietic stem cell transplantation, less is known about its significance in newly diagnosed multiple myeloma. We studied absolute lymphocyte (ALC) and absolute monocyte (AMC) counts at the time of treatment initiation and 1 month thereafter in 771 newly diagnosed patients. Two hundred and thirty‐four patients (31%) had evidence of immune dysregulation at baseline (abnormal biomarkers). Eighty‐seven of these patients (37%) recovered normal biomarkers at 1 month (early immune reconstitution). The absence of immune dysregulation at baseline (compared to the presence thereof) was associated with better overall survival (HR 0.77, 95% CI 0.61‐0.97, P = 0.025, n = 771). The absence of immune dysregulation at 1 month (compared to the persistence or development thereof) was associated with better overall survival (HR 0.63, 95% CI 0.50‐0.80, P < 0.001, n = 771). Early immune reconstitution (compared to the persistence or development of immune dysregulation) was associated with better overall survival (HR 0.62, 95% CI 0.43‐0.92, P = 0.016, n = 771). Cytogenetic high‐risk disease was negatively, and treatment with immunomodulators positively, associated with early immune reconstitution. The presence or development of immune dysregulation in newly diagnosed multiple myeloma is an independent risk factor. The favorable impact of early immune reconstitution suggests immune dysregulation to be a potentially modifiable risk factor that may be exploited for therapeutic benefit.

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“…Minimally invasive protocols could provide drug-response information in co-culture systems. This could maintain leukemia and multiple myeloma cells for a longer cultivating time and enhance the screening capabilities of patient samples [45][46][47]. Snijder and colleagues investigated the clinical impact of a newly developed single-cell image analysis technology platform that operates using a combination of multi-parametric immunofluorescence and high-throughput automated microscopy [48].…”

Section: Advances Of Single-cell Functional Studiesmentioning

confidence: 99%

Precision Medicine Concepts in T-Cell Lymphoma

Staber¹

2019

Peripheral T-Cell Lymphomas

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Modern oncology witnesses an increasing number of new effective anticancer drugs targeting specific oncogenic pathways. Despite these advances, real-world experience with targeted single agents is disappointing since drug resistance usually occurs after a short time. This is particularly true for patients with refractory or relapsed T-cell lymphoma (TCL) who so far could not benefit from novel agents and demonstrate a short survival time of only 3 months. The novel genetic information gained from genome-wide high-throughput techniques has greatly improved our understanding of TCL. However, if precision medicine strategies are based solely on genetics, it runs into two major challenges: (1) the heterogeneity within the cancer of an individual patient and (2) the incomplete understanding of the degree of contribution of a specific mutation to a tumor phenotype. Next-generation functional drug screening (ngFDS) aims to address these problems. Studies that proof the clinical utility of ngFDS are currently limited. The following chapter aims to discuss recent advances of ngFDS and to line out its potential for TCL patients.

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An Ex Vivo Platform for the Prediction of Clinical Response in Multiple Myeloma

Cited by 59 publications

References 51 publications

Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression

Measurement of ex vivo resistance to proteasome inhibitors, IMiDs, and daratumumab during multiple myeloma progression

Peripheral blood biomarkers of early immune reconstitution in newly diagnosed multiple myeloma

Precision Medicine Concepts in T-Cell Lymphoma

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