Publications by authors named "Mahrukh Huseni"

16 Publications

  • Page 1 of 1

Efficacy and Safety of Atezolizumab Plus Bevacizumab Following Disease Progression on Atezolizumab or Sunitinib Monotherapy in Patients with Metastatic Renal Cell Carcinoma in IMmotion150: A Randomized Phase 2 Clinical Trial.

Eur Urol 2021 May 5;79(5):665-673. Epub 2021 Mar 5.

Beth Israel Deaconess Medical Center, Boston, MA, USA.

Background: The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively.

Objective: To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC.

Design, Setting, And Participants: IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab.

Intervention: Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy.

Outcome Measurements And Statistical Analysis: The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods.

Results And Limitations: Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19-37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6-13.7) mo. The median event follow-up duration was 19.4 (12.9-21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors.

Conclusions: The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC.

Patient Summary: Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.
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http://dx.doi.org/10.1016/j.eururo.2021.01.003DOI Listing
May 2021

Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade.

Cancer Cell 2020 12 5;38(6):803-817.e4. Epub 2020 Nov 5.

Vanderbilt University Medical Center, Nashville, TN, USA.

Integrated multi-omics evaluation of 823 tumors from advanced renal cell carcinoma (RCC) patients identifies molecular subsets associated with differential clinical outcomes to angiogenesis blockade alone or with a checkpoint inhibitor. Unsupervised transcriptomic analysis reveals seven molecular subsets with distinct angiogenesis, immune, cell-cycle, metabolism, and stromal programs. While sunitinib and atezolizumab + bevacizumab are effective in subsets with high angiogenesis, atezolizumab + bevacizumab improves clinical benefit in tumors with high T-effector and/or cell-cycle transcription. Somatic mutations in PBRM1 and KDM5C associate with high angiogenesis and AMPK/fatty acid oxidation gene expression, while CDKN2A/B and TP53 alterations associate with increased cell-cycle and anabolic metabolism. Sarcomatoid tumors exhibit lower prevalence of PBRM1 mutations and angiogenesis markers, frequent CDKN2A/B alterations, and increased PD-L1 expression. These findings can be applied to molecularly stratify patients, explain improved outcomes of sarcomatoid tumors to checkpoint blockade versus antiangiogenics alone, and develop personalized therapies in RCC and other indications.
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http://dx.doi.org/10.1016/j.ccell.2020.10.011DOI Listing
December 2020

Atezolizumab plus Bevacizumab Versus Sunitinib for Patients with Untreated Metastatic Renal Cell Carcinoma and Sarcomatoid Features: A Prespecified Subgroup Analysis of the IMmotion151 Clinical Trial.

Eur Urol 2021 May 9;79(5):659-662. Epub 2020 Jul 9.

Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.

Patients with metastatic renal cell carcinoma with sarcomatoid features (sRCC) have a poor prognosis and have shown limited responsiveness to inhibition of the VEGF pathway. We conducted a prespecified analysis of the randomised, phase 3 IMmotion151 trial in previously untreated patients with advanced or metastatic RCC to assess the effectiveness of atezolizumab + bevacizumab versus sunitinib in a subgroup of patients with sarcomatoid features. Patients whose tumour had any component of sarcomatoid features were included and received atezolizumab + bevacizumab (n = 68) or sunitinib (n = 74). Baseline characteristics were similar between the groups. Median progression-free survival was significantly longer in the group receiving atezolizumab + bevacizumab overall (8.3 vs 5.3 mo; hazard ratio [HR] 0.52 95% confidence interval [CI] 0.34-0.79) and in the subset of patients with PD-L1-positive tumours (8.6 vs 5.6 mo; HR 0.45, 95% CI 0.26-0.77). More patients receiving atezolizumab + bevacizumab achieved an objective response (49% vs 14%), including complete responses (10% vs 3%), and reported greater symptom improvements versus sunitinib. Safety was consistent with the known profiles of each drug and with that reported in the overall safety-evaluable population of IMmotion151. This analysis supports enhanced activity of atezolizumab + bevacizumab in patients with sRCC. PATIENT SUMMARY: In this report, we looked at patients with a specific type of kidney cancer (tumours with sarcomatoid features) that has been hard to treat. A treatment with two drugs (atezolizumab and bevacizumab) appeared to help patients live longer without the disease getting worse than another drug (sunitinib) that is often used. Patients who took the two drugs also said they were better able to carry out their everyday activities than patients who took sunitinib. The combination of these two drugs may work better in patients with this type of advanced kidney cancer.
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http://dx.doi.org/10.1016/j.eururo.2020.06.021DOI Listing
May 2021

High systemic and tumor-associated IL-8 correlates with reduced clinical benefit of PD-L1 blockade.

Nat Med 2020 05 11;26(5):693-698. Epub 2020 May 11.

Genentech, San Francisco, CA, USA.

Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade , this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8 T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.
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http://dx.doi.org/10.1038/s41591-020-0860-1DOI Listing
May 2020

Peripheral T cell expansion predicts tumour infiltration and clinical response.

Nature 2020 03 26;579(7798):274-278. Epub 2020 Feb 26.

ArsenalBio, South San Francisco, CA, USA.

Despite the resounding clinical success in cancer treatment of antibodies that block the interaction of PD1 with its ligand PDL1, the mechanisms involved remain unknown. A major limitation to understanding the origin and fate of T cells in tumour immunity is the lack of quantitative information on the distribution of individual clonotypes of T cells in patients with cancer. Here, by performing deep single-cell sequencing of RNA and T cell receptors in patients with different types of cancer, we survey the profiles of various populations of T cells and T cell receptors in tumours, normal adjacent tissue, and peripheral blood. We find clear evidence of clonotypic expansion of effector-like T cells not only within the tumour but also in normal adjacent tissue. Patients with gene signatures of such clonotypic expansion respond best to anti-PDL1 therapy. Notably, expanded clonotypes found in the tumour and normal adjacent tissue can also typically be detected in peripheral blood, which suggests a convenient approach to patient identification. Analyses of our data together with several external datasets suggest that intratumoural T cells, especially in responsive patients, are replenished with fresh, non-exhausted replacement cells from sites outside the tumour, suggesting continued activity of the cancer immunity cycle in these patients, the acceleration of which may be associated with clinical response.
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http://dx.doi.org/10.1038/s41586-020-2056-8DOI Listing
March 2020

Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial.

Lancet 2019 06 9;393(10189):2404-2415. Epub 2019 May 9.

Genentech, Inc, South San Francisco, CA, USA.

Background: A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma.

Methods: In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821.

Findings: Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation.

Interpretation: Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.

Funding: F Hoffmann-La Roche Ltd and Genentech Inc.
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http://dx.doi.org/10.1016/S0140-6736(19)30723-8DOI Listing
June 2019

Phase I study of the anti-α5β1 monoclonal antibody MINT1526A with or without bevacizumab in patients with advanced solid tumors.

Cancer Chemother Pharmacol 2018 08 15;82(2):339-351. Epub 2018 Jun 15.

California Cancer Associates for Research & Excellence, Encinitas, CA, USA.

Purpose: MINT1526A is a monoclonal antibody that blocks the interaction of integrin alpha 5 beta 1 (α5β1) with its extracellular matrix ligands. This phase I study evaluated the safety and pharmacokinetics of MINT1526A with or without bevacizumab in patients with advanced solid tumors.

Methods: MINT1526A was administered every 3 weeks (Q3W) as monotherapy (arm 1) or in combination with bevacizumab 15 mg/kg, Q3W (arm 2). Each arm included a 3 + 3 dose-escalation stage and a dose-expansion stage.

Results: Twenty-four patients were enrolled in arm 1 (dose range 2-30 mg/kg) and 30 patients were enrolled in arm 2 (dose range 3-15 mg/kg). Monocyte α5β1 receptor occupancy was saturated at a dose of 15 mg/kg. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached in either arm. The most common adverse events, regardless of causality, included abdominal pain (25%), diarrhea (25%), nausea (21%), vomiting (21%), and fatigue (21%) in arm 1 and nausea (40%), fatigue (33%), vomiting (30%), dehydration (30%), headache (30%), and hypertension (30%) in arm 2. No grade ≥ 3 bleeding events were observed in either arm. No confirmed partial responses (PR) were observed in arm 1. In arm 2, one patient with thymic carcinoma experienced a confirmed PR and two patients with hepatocellular carcinoma (HCC) experienced durable minor radiographic responses.

Conclusions: MINT1526A, with or without bevacizumab, was well-tolerated. Preliminary evidence of combination efficacy, including in patients with HCC, was observed, but cannot be distinguished from bevacizumab monotherapy in this phase I study.
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http://dx.doi.org/10.1007/s00280-018-3622-8DOI Listing
August 2018

Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.

Nat Med 2018 06 4;24(6):749-757. Epub 2018 Jun 4.

Genentech, Inc., South San Francisco, CA, USA.

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.
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http://dx.doi.org/10.1038/s41591-018-0053-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721896PMC
June 2018

CD8+ T cell infiltration in breast and colon cancer: A histologic and statistical analysis.

PLoS One 2018 10;13(1):e0190158. Epub 2018 Jan 10.

Department of Cancer Immunology, Genentech, Inc., South San Francisco, California, United States of America.

The prevalence of cytotoxic tumor infiltrating lymphocytes (TILs) has demonstrated prognostic value in multiple tumor types. In particular, CD8 counts (in combination with CD3 and CD45RO) have been shown to be superior to traditional UICC staging in colon cancer patients and higher total CD8 counts have been associated with better survival in breast cancer patients. However, immune infiltrate heterogeneity can lead to potentially significant misrepresentations of marker prevalence in routine histologic sections. We examined step sections of breast and colorectal cancer samples for CD8+ T cell prevalence by standard chromogenic immunohistochemistry to determine marker variability and inform practice of T cell biomarker assessment in formalin-fixed, paraffin-embedded (FFPE) tissue samples. Stained sections were digitally imaged and CD8+ lymphocytes within defined regions of interest (ROI) including the tumor and surrounding stroma were enumerated. Statistical analyses of CD8+ cell count variability using a linear model/ANOVA framework between patients as well as between levels within a patient sample were performed. Our results show that CD8+ T-cell distribution is highly homogeneous within a standard tissue sample in both colorectal and breast carcinomas. As such, cytotoxic T cell prevalence by immunohistochemistry on a single level or even from a subsample of biopsy fragments taken from that level can be considered representative of cytotoxic T cell infiltration for the entire tumor section within the block. These findings support the technical validity of biomarker strategies relying on CD8 immunohistochemistry.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190158PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761898PMC
February 2018

Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies.

Sci Transl Med 2015 May;7(287):287ra70

Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.

Bispecific antibodies and antibody fragments in various formats have been explored as a means to recruit cytolytic T cells to kill tumor cells. Encouraging clinical data have been reported with molecules such as the anti-CD19/CD3 bispecific T cell engager (BiTE) blinatumomab. However, the clinical use of many reported T cell-recruiting bispecific modalities is limited by liabilities including unfavorable pharmacokinetics, potential immunogenicity, and manufacturing challenges. We describe a B cell-targeting anti-CD20/CD3 T cell-dependent bispecific antibody (CD20-TDB), which is a full-length, humanized immunoglobulin G1 molecule with near-native antibody architecture constructed using "knobs-into-holes" technology. CD20-TDB is highly active in killing CD20-expressing B cells, including primary patient leukemia and lymphoma cells both in vitro and in vivo. In cynomolgus monkeys, CD20-TDB potently depletes B cells in peripheral blood and lymphoid tissues at a single dose of 1 mg/kg while demonstrating pharmacokinetic properties similar to those of conventional monoclonal antibodies. CD20-TDB also exhibits activity in vitro and in vivo in the presence of competing CD20-targeting antibodies. These data provide rationale for the clinical testing of CD20-TDB for the treatment of CD20-expressing B cell malignancies.
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http://dx.doi.org/10.1126/scitranslmed.aaa4802DOI Listing
May 2015

The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function.

Cancer Cell 2014 Dec 26;26(6):923-937. Epub 2014 Nov 26.

Department of Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address:

Tumors constitute highly suppressive microenvironments in which infiltrating T cells are "exhausted" by inhibitory receptors such as PD-1. Here we identify TIGIT as a coinhibitory receptor that critically limits antitumor and other CD8(+) T cell-dependent chronic immune responses. TIGIT is highly expressed on human and murine tumor-infiltrating T cells, and, in models of both cancer and chronic viral infection, antibody coblockade of TIGIT and PD-L1 synergistically and specifically enhanced CD8(+) T cell effector function, resulting in significant tumor and viral clearance, respectively. This effect was abrogated by blockade of TIGIT's complementary costimulatory receptor, CD226, whose dimerization is disrupted upon direct interaction with TIGIT in cis. These results define a key role for TIGIT in inhibiting chronic CD8(+) T cell-dependent responses.
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http://dx.doi.org/10.1016/j.ccell.2014.10.018DOI Listing
December 2014

Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy.

J Clin Invest 2013 Sep 15;123(9):3997-4009. Epub 2013 Aug 15.

Genentech Inc., South San Francisco, California 94080, USA.

Many oncology drugs are administered at their maximally tolerated dose without the knowledge of their optimal efficacious dose range. In this study, we describe a multifaceted approach that integrated preclinical and clinical data to identify the optimal dose for an antiangiogenesis agent, anti-EGFL7. EGFL7 is an extracellular matrix-associated protein expressed in activated endothelium. Recombinant EGFL7 protein supported EC adhesion and protected ECs from stress-induced apoptosis. Anti-EGFL7 antibodies inhibited both of these key processes and augmented anti-VEGF-mediated vascular damage in various murine tumor models. In a genetically engineered mouse model of advanced non-small cell lung cancer, we found that anti-EGFL7 enhanced both the progression-free and overall survival benefits derived from anti-VEGF therapy in a dose-dependent manner. In addition, we identified a circulating progenitor cell type that was regulated by EGFL7 and evaluated the response of these cells to anti-EGFL7 treatment in both tumor-bearing mice and cancer patients from a phase I clinical trial. Importantly, these preclinical efficacy and clinical biomarker results enabled rational selection of the anti-EGFL7 dose currently being tested in phase II clinical trials.
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http://dx.doi.org/10.1172/JCI67892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754254PMC
September 2013

Development of a robust flow cytometry-based pharmacodynamic assay to detect phospho-protein signals for phosphatidylinositol 3-kinase inhibitors in multiple myeloma.

J Transl Med 2013 Mar 23;11:76. Epub 2013 Mar 23.

Genentech Inc, South San Francisco, CA 94080, USA.

Background: The phosphatidylinositol 3-kinase (PI3K) pathway plays an important role in multiple myeloma (MM), a blood cancer associated with uncontrolled proliferation of bone marrow plasma cells. This study aimed to develop a robust clinical pharmacodynamic (PD) assay to measure the on-target PD effects of the selective PI3K inhibitor GDC-0941 in MM patients.

Methods: We conducted an in vitro drug wash-out study to evaluate the feasibility of biochemical approaches in measuring the phosphorylation of S6 ribosomal protein (S6), one of the commonly used PD markers for PI3K pathway inhibition. We then developed a 7-color phospho-specific flow cytometry assay, or phospho flow assay, to measure the phosphorylation state of intracellular S6 in bone marrow aspirate (BMA) and peripheral blood (PB). Integrated mean fluorescence intensity (iMFI) was used to calculate fold changes of phosphorylation. Assay sensitivity was evaluated by comparing phospho flow with Meso Scale Discovery (MSD) and immunohistochemistry (IHC) assays. Finally, a sample handling method was developed to maintain the integrity of phospho signal during sample shipping and storage to ensure clinical application.

Results: The phospho flow assay provided single-cell PD monitoring of S6 phosphorylation in tumor and surrogate cells using fixed BMA and PB, assessing pathway modulation in response to GDC-0941 with sensitivity similar to that of MSD assay. The one-shot sample fixation and handling protocol herein demonstrated exceptional preservation of protein phosphorylation. In contrast, the IHC assay was less sensitive in terms of signal quantification while the biochemical approach (MSD) was less suitable to assess PD activities due to the undesirable impact associated with cell isolation on the protein phosphorylation in tumor cells.

Conclusions: We developed a robust PD biomarker assay for the clinical evaluation of PI3K inhibitors in MM, allowing one to decipher the PD response in a relevant cell population. To our knowledge, this is the first report of an easily implemented clinical PD assay that incorporates an unbiased one-shot sample handling protocol, all (staining)-in-one (tube) phospho flow staining protocol, and an integrated modified data analysis for PD monitoring of kinase inhibitors in relevant cell populations in BMA and PB. The methods described here ensure a real-time, reliable and reproducible PD readout, which can provide information for dose selection as well as help to identify optimal combinations of targeted agents in early clinical trials.
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http://dx.doi.org/10.1186/1479-5876-11-76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623880PMC
March 2013

CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma.

Clin Cancer Res 2008 May;14(9):2775-84

Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Purpose: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models.

Experimental Design: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice.

Results: CS1 mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1 antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like T cells, and CD8+ T cells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice.

Conclusions: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma.
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http://dx.doi.org/10.1158/1078-0432.CCR-07-4246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433038PMC
May 2008