Publications by authors named "Alfred Garfall"

37 Publications

Femtomolar SARS-CoV-2 Antigen Detection Using the Microbubbling Digital Assay with Smartphone Readout Enables Antigen Burden Quantitation and Dynamics Tracking.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

Background: Little is known about the dynamics of SARS-CoV-2 antigen burden in respiratory samples in different patient populations at different stages of infection. Current rapid antigen tests cannot quantitate and track antigen dynamics with high sensitivity and specificity in respiratory samples.

Methods: We developed and validated an ultra-sensitive SARS-CoV-2 antigen assay with smartphone readout using the Microbubbling Digital Assay previously developed by our group, which is a platform that enables highly sensitive detection and quantitation of protein biomarkers. A computer vision-based algorithm was developed for microbubble smartphone image recognition and quantitation. A machine learning-based classifier was developed to classify the smartphone images based on detected microbubbles. Using this assay, we tracked antigen dynamics in serial swab samples from COVID patients hospitalized in ICU and immunocompromised COVID patients.

Results: The limit of detection (LOD) of the Microbubbling SARS-CoV-2 Antigen Assay was 0.5 pg/mL (10.6 fM) recombinant nucleocapsid (N) antigen or 4000 copies/mL inactivated SARS-CoV-2 virus in nasopharyngeal (NP) swabs, comparable to many rRT-PCR methods. The assay had high analytical specificity towards SARS-CoV-2. Compared to EUA-approved rRT-PCR methods, the Microbubbling Antigen Assay demonstrated a positive percent agreement (PPA) of 97% (95% confidence interval (CI), 92-99%) in symptomatic individuals within 7 days of symptom onset and positive SARS-CoV-2 nucleic acid results, and a negative percent agreement (NPA) of 97% (95% CI, 94-100%) in symptomatic and asymptomatic individuals with negative nucleic acid results. Antigen positivity rate in NP swabs gradually decreased as days-after-symptom-onset increased, despite persistent nucleic acid positivity of the same samples. The computer vision and machine learning-based automatic microbubble image classifier could accurately identify positives and negatives, based on microbubble counts and sizes. Total microbubble volume, a potential marker of antigen burden, correlated inversely with Ct values and days-after-symptom-onset. Antigen was detected for longer periods of time in immunocompromised patients with hematologic malignancies, compared to immunocompetent individuals. Simultaneous detectable antigens and nucleic acids may indicate the presence of replicating viruses in patients with persistent infections.

Conclusions: The Microbubbling SARS-CoV-2 Antigen Assay enables sensitive and specific detection of acute infections, and quantitation and tracking of antigen dynamics in different patient populations at various stages of infection. With smartphone compatibility and automated image processing, the assay is well-positioned to be adapted for point-of-care diagnosis and to explore the clinical implications of antigen dynamics in future studies.
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http://dx.doi.org/10.1101/2021.03.17.21253847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010739PMC
March 2021

CD8 T cells compensate for impaired humoral immunity in COVID-19 patients with hematologic cancer.

Res Sq 2021 Feb 2. Epub 2021 Feb 2.

Cancer patients have increased morbidity and mortality from Coronavirus Disease 2019 (COVID-19), but the underlying immune mechanisms are unknown. In a cohort of 100 cancer patients hospitalized for COVID-19 at the University of Pennsylvania Health System, we found that patients with hematologic cancers had a significantly higher mortality relative to patients with solid cancers after accounting for confounders including ECOG performance status and active cancer status. We performed flow cytometric and serologic analyses of 106 cancer patients and 113 non-cancer controls from two additional cohorts at Penn and Memorial Sloan Kettering Cancer Center. Patients with solid cancers exhibited an immune phenotype similar to non-cancer patients during acute COVID-19 whereas patients with hematologic cancers had significant impairment of B cells and SARS-CoV-2-specific antibody responses. High dimensional analysis of flow cytometric data revealed 5 distinct immune phenotypes. An immune phenotype characterized by CD8 T cell depletion was associated with a high viral load and the highest mortality of 71%, among all cancer patients. In contrast, despite impaired B cell responses, patients with hematologic cancers and preserved CD8 T cells had a lower viral load and mortality. These data highlight the importance of CD8 T cells in acute COVID-19, particularly in the setting of impaired humoral immunity. Further, depletion of B cells with anti-CD20 therapy resulted in almost complete abrogation of SARS-CoV-2-specific IgG and IgM antibodies, but was not associated with increased mortality compared to other hematologic cancers, when adequate CD8 T cells were present. Finally, higher CD8 T cell counts were associated with improved overall survival in patients with hematologic cancers. Thus, CD8 T cells likely compensate for deficient humoral immunity and influence clinical recovery of COVID-19. These observations have important implications for cancer and COVID-19-directed treatments, immunosuppressive therapies, and for understanding the role of B and T cells in acute COVID-19.
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http://dx.doi.org/10.21203/rs.3.rs-162289/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872363PMC
February 2021

Multiple Myeloma, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2020 12 2;18(12):1685-1717. Epub 2020 Dec 2.

28National Comprehensive Cancer Network.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.
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http://dx.doi.org/10.6004/jnccn.2020.0057DOI Listing
December 2020

Axicabtagene ciloleucel for CD19+ plasmablastic lymphoma.

Am J Hematol 2020 01 25;95(1):E28-E30. Epub 2019 Nov 25.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1002/ajh.25682DOI Listing
January 2020

NCCN Guidelines Insights: Multiple Myeloma, Version 1.2020.

J Natl Compr Canc Netw 2019 10;17(10):1154-1165

National Comprehensive Cancer Network.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.
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http://dx.doi.org/10.6004/jnccn.2019.0049DOI Listing
October 2019

Multitargeted CAR T-cell therapy in multiple myeloma.

Lancet Haematol 2019 10 1;6(10):e494-e495. Epub 2019 Aug 1.

Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(19)30165-6DOI Listing
October 2019

Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma.

J Clin Oncol 2019 08 12;37(22):1946-1955. Epub 2019 Jun 12.

4Washington University, St Louis, MO.

Purpose: Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs.

Patients And Methods: Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs.

Results: Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib ( = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; < .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank = .01) and overall survival (log-rank < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications.

Conclusion: CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.
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http://dx.doi.org/10.1200/JCO.19.00231DOI Listing
August 2019

Immunotherapy in Multiple Myeloma: Accelerating on the Path to the Patient.

Clin Lymphoma Myeloma Leuk 2019 06 20;19(6):332-344. Epub 2019 Feb 20.

Winship Cancer Institute of Emory University, Atlanta, GA. Electronic address:

Multiple myeloma (MM) is a plasma cell malignancy characterized by impaired immune surveillance mechanisms, such as altered antibody production, dysregulation of T cell and natural killer cell proliferation and activation, disruption of antigen presentation processes, and upregulation of checkpoint and immunosuppressive mediators. New and emerging immunotherapeutic agents, such as chimeric antigen receptor (CAR)-engineered T-cell therapies, vaccines, antibody-based therapy, and checkpoint inhibitors, have been developed as a means to target evasion tactics of MM. Herein we summarize the proceedings of "Immunotherapy in Multiple Myeloma: Accelerating on the Path to the Patient," a workshop held in Havana, Cuba, with contributions from 18 expert hematologic oncologists from the United States, European Union, and Cuba, as well as patient advocacy and industry representatives. The goal of the workshop was to evaluate and discuss key topics and issues regarding development and use of immunotherapies in MM and to collaborate on improving patient outcomes. Clinical significance of recent advances in immunotherapies in MM were discussed, in addition to their current status and therapeutic potential, key issues from various regional perspectives, and opportunities for collaboration to improve MM patient outcomes. In this review we summarize expert presentations on cellular (CAR T cell, allogeneic stem cell transplantation, and vaccine) therapies, antibody-based (daratumumab, elotuzumab, checkpoint inhibitor, anti-cluster of differentiation 28 antibody) therapies, genomics and immunotherapy, and biomarkers of response.
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http://dx.doi.org/10.1016/j.clml.2019.02.004DOI Listing
June 2019

B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma.

J Clin Invest 2019 03 21;129(6):2210-2221. Epub 2019 Mar 21.

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM).

Methods: We conducted a phase I study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required.

Results: CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product.

Conclusion: CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients.

Trial Registration: NCT02546167.

Funding: University of Pennsylvania-Novartis Alliance and NIH.
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http://dx.doi.org/10.1172/JCI126397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546468PMC
March 2019

RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation.

Leukemia 2019 08 13;33(8):2006-2021. Epub 2019 Feb 13.

Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation, and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.
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http://dx.doi.org/10.1038/s41375-019-0403-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687534PMC
August 2019

Chimeric antigen receptor T cell immunotherapy for multiple myeloma: A review of current data and potential clinical applications.

Am J Hematol 2019 05 25;94(S1):S28-S33. Epub 2019 Feb 25.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.

Multiple myeloma (MM) is a malignant plasma cell disorder that remains incurable for most patients despite significant improvements achieved with modern therapy. Tumor evasion is a key process in the pathogenesis of MM and a compromised immune system is associated with more aggressive forms of the disease. In contrast, the emergence of myeloma-specific immune responses after both autologous and allogeneic stem cell transplantation is associated with better prognosis. Adoptive T cell therapies may improve specific anti-myeloma immunity resulting in long-lasting remissions. CAR T cell therapies for MM are at an early stage of clinical development. To date, anti-BCMA CAR T cells have shown the greatest results in early-phase clinical trials. Toxicities have included cytokine release syndrome (CRS) and neurotoxicity. Current areas of research in CAR T cell therapies include the use of gene-editing to enhance their effectiveness and safety, the integration of CAR T cells with other therapies (immunomodulatory drugs, checkpoint inhibitors) and CAR T cells to target multiple antigens.
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http://dx.doi.org/10.1002/ajh.25428DOI Listing
May 2019

Acute Liver Failure Associated With Pomalidomide Therapy for Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2018 08 26;18(8):e337-e338. Epub 2018 May 26.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address:

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http://dx.doi.org/10.1016/j.clml.2018.05.012DOI Listing
August 2018

Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma.

JCI Insight 2018 04 19;3(8). Epub 2018 Apr 19.

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019).

Methods: Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS).

Results: ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently.

Conclusion: CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells.

Trial Registration: Clinicaltrials.gov identifier NCT02135406.

Funding: Novartis, NIH, Conquer Cancer Foundation.
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http://dx.doi.org/10.1172/jci.insight.120505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931130PMC
April 2018

Carfilzomib-Associated Cardiovascular Adverse Events: A Systematic Review and Meta-analysis.

JAMA Oncol 2018 Mar 8;4(3):e174519. Epub 2018 Mar 8.

Division of Hematology and Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

Importance: Cardiovascular adverse events (CVAE) with carfilzomib in patients with multiple myeloma can be potentially life-threatening and remain incompletely characterized. We performed the first systematic review and meta-analysis of carfilzomib-associated CVAE.

Objective: To determine the incidence of carfilzomib-associated CVAE and to compare the rates of carfilzomib CVAE among different doses and companion therapies.

Data Sources: PubMed, EMBASE, Web of Science, and clinicaltrials.gov were queried for the keywords "carfilzomib," "Kyprolis," and "PX-171" through January 1, 2017.

Study Selection: Phase 1 to 3 prospective clinical trials of carfilzomib in patients with multiple myeloma with evaluable toxic effects data were eligible for meta-analysis.

Data Extraction And Synthesis: Data were independently extracted by 2 reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Pooled incidence rates and relative risks (for randomized trials) and 95% confidence intervals were calculated using a random effects model. Subgroup analyses were performed to assess study-level characteristics associated with CVAE.

Main Outcomes And Measures: Cardiovascular adverse events were defined as heart failure, hypertension, ischemia, and arrhythmia. All-grade and grades 3 or higher AEs and study characteristics were recorded.

Results: A total of 514 studies were assessed for eligibility. Of those, 24 studies were eligible, including a total of 2594 patients with multiple myeloma. All-grade and grades 3 and higher CVAE were seen in 617 (18.1%) and 274 (8.2%), respectively. Phase 2 or 3 studies and carfilzomib doses of 45 mg/m2 or higher were associated with high-grade CVAE. Median age older than 65 years, prior myeloma therapies, and concurrent myeloma therapies were not associated with CVAE. For the 3 randomized clinical trials, the summary relative risk of all-grade and grade 3 or higher CVAE for patients receiving carfilzomib compared with noncarfilzomib-receiving control patients were 1.8 and 2.2, respectively.

Conclusions And Relevance: Carfilzomib was associated with a significant incidence of CVAE, with higher rates seen with higher doses of carfilzomib. Phase 1 studies may be underdetecting CVAE. Future studies are needed to identify patients at high risk for CVAE, develop optimal monitoring strategies, and explore strategies to mitigate these risks.
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http://dx.doi.org/10.1001/jamaoncol.2017.4519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885859PMC
March 2018

Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients.

Sci Immunol 2016 Aug 5;1(2). Epub 2016 Aug 5.

The Wistar Institute, Philadelphia, PA, 19104, USA.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) are important regulators of immune responses in cancer and have been directly implicated in promotion of tumor progression. However, the heterogeneity of these cells and lack of distinct markers hampers the progress in understanding of the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation we determined that low density PMN-MDSC and high density neutrophils from the same cancer patients had a distinct gene profile. Most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Surprisingly, low-density lipoprotein (LDL) was one of the most increased regulators and its receptor oxidized LDL receptor 1 was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor 1 (LOX-1) encoded by was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5-15% of total neutrophils in cancer patients and 15-50% of neutrophils in tumor tissues were LOX-1. In contrast to their LOX-1 counterparts, LOX-1 neutrophils had gene signature, potent immune suppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSC. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSC. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insight to the biology and potential therapeutic targeting of these cells.
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http://dx.doi.org/10.1126/sciimmunol.aaf8943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391495PMC
August 2016

Matching at Human Leukocyte Antigen-C Improved the Outcomes after Double Umbilical Cord Blood Transplantation for Recipients of Two to Four of Six Human Leukocyte Antigen-Matched Grafts.

Biol Blood Marrow Transplant 2017 01 29;23(1):126-133. Epub 2016 Oct 29.

Massachusetts General Hospital, Boston, Massachusetts.

We studied the effect of HLA-C matching in 515 patients after double umbilical cord blood (UCB) transplantation. After HLA matching HLA-A, -B, and -DRB1 at the allele level, we scored patients according to number of donor-recipient HLA-C matches at 4 possible loci: 2 from each donor unit, at the allele level. Given a direct interaction between HLA-A, -B, and -DRB1 matching and HLA-C score, we analyzed HLA-C matching in those receiving at least 1 2/6 to 4/6 HLA-matched unit (n = 389) versus those receiving only 5/6 or 6/6-matched units (n = 126). In those with at least 1 2/6 to 4/6 HLA-matched unit, a better HLA-C matching score was associated with significantly lower risk of death of any cause and nonrelapse mortality and better disease-free survival. There was no association with the risk of relapse, acute and chronic graft-versus-host disease, and hematopoietic recovery. In contrast, among patients receiving only allele-level 5/6 or 6/6 HLA-matched UCB units, HLA-C match had no demonstrable effect on any outcome. For patients receiving at least 1 allele-level 2/6 to 4/6 HLA-matched UCB unit, matching at HLA-C reduces nonrelapse mortality and improves survival.
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http://dx.doi.org/10.1016/j.bbmt.2016.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510875PMC
January 2017

Cellular and vaccine immunotherapy for multiple myeloma.

Hematology Am Soc Hematol Educ Program 2016 Dec;2016(1):521-527

Division of Hematology-Oncology and the Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Allogeneic hematopoietic cell transplantation and donor lymphocyte infusion for multiple myeloma (MM) can induce graft-versus-myeloma immunity and long-term survivorship, but limited efficacy and associated toxicities have prevented its widespread use. Cellular immunotherapies and vaccines seek to induce more specific, reliable, and potent antimyeloma immune responses with less treatment-related risk than is possible with allogeneic transplantation. Advances in molecular biology, and basic and applied immunology, have led to promising approaches such as genetically engineered T cells with chimeric antigen receptors and T-cell receptors targeting myeloma-specific epitopes, vaccine primed ex vivo expanded autologous T cells, expanded marrow-infiltrating lymphocytes, and plasma cell/dendritic cell fusion vaccines. The addition of these emerging therapies to immunomodulatory drugs and inhibitors of programmed death-1 T-cell regulatory pathways are poised to improve outcome for our patients with myeloma.
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http://dx.doi.org/10.1182/asheducation-2016.1.521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142464PMC
December 2016

Origin and Role of a Subset of Tumor-Associated Neutrophils with Antigen-Presenting Cell Features in Early-Stage Human Lung Cancer.

Cancer Cell 2016 07 30;30(1):120-135. Epub 2016 Jun 30.

Division of Thoracic Surgery, Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Based on studies in mouse tumor models, granulocytes appear to play a tumor-promoting role. However, there are limited data about the phenotype and function of tumor-associated neutrophils (TANs) in humans. Here, we identify a subset of TANs that exhibited characteristics of both neutrophils and antigen-presenting cells (APCs) in early-stage human lung cancer. These APC-like "hybrid neutrophils," which originate from CD11b(+)CD15(hi)CD10(-)CD16(low) immature progenitors, are able to cross-present antigens, as well as trigger and augment anti-tumor T cell responses. Interferon-γ and granulocyte-macrophage colony-stimulating factor are requisite factors in the tumor that, working through the Ikaros transcription factor, synergistically exert their APC-promoting effects on the progenitors. Overall, these data demonstrate the existence of a specialized TAN subset with anti-tumor capabilities in human cancer.
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http://dx.doi.org/10.1016/j.ccell.2016.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945447PMC
July 2016

The Promise of Chimeric Antigen Receptor Engineered T Cells in the Treatment of Hematologic Malignancies.

Cancer J 2016 Jan-Feb;22(1):27-33

From the Division of Hematology/Oncology, Department of Medicine and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Relapsed and refractory hematologic malignancies have a very poor prognosis. Chimeric antigen receptor T cells are emerging as a powerful therapy in this setting. Early clinical trials of genetically modified T cells for the treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia have shown high complete response rates in patients with few therapeutic options. Exploration is ongoing for other hematologic malignancies including multiple myeloma, acute myeloid leukemia, and Hodgkin lymphoma (HL). At the same time, the design and production of chimeric antigen receptor T cells are being advanced so that this therapy can be more widely utilized. Cytokine release syndrome and neurotoxicity are common, but they are treatable and fully reversible. This review will review available data as well as future developments and challenges in the field.
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http://dx.doi.org/10.1097/PPO.0000000000000166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742356PMC
November 2016

Combined deletion of cathepsin protease family members reveals compensatory mechanisms in cancer.

Genes Dev 2016 Jan;30(2):220-32

Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA; Department of Oncology, University of Lausanne, CH-1066, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH-1066, Lausanne, Switzerland.

Proteases are important for regulating multiple tumorigenic processes, including angiogenesis, tumor growth, and invasion. Elevated protease expression is associated with poor patient prognosis across numerous tumor types. Several multigene protease families have been implicated in cancer, including cysteine cathepsins. However, whether individual family members have unique roles or are functionally redundant remains poorly understood. Here we demonstrate stage-dependent effects of simultaneously deleting cathepsin B (CtsB) and CtsS in a murine pancreatic neuroendocrine tumor model. Early in tumorigenesis, the double knockout results in an additive reduction in angiogenic switching, whereas at late stages, several tumorigenic phenotypes are unexpectedly restored to wild-type levels. We identified CtsZ, which is predominantly supplied by tumor-associated macrophages, as the compensatory protease that regulates the acquired tumor-promoting functions of lesions deficient in both CtsB and CtsS. Thus, deletion of multiple cathepsins can lead to stage-dependent, compensatory mechanisms in the tumor microenvironment, which has potential implications for the clinical consideration of selective versus pan-family cathepsin inhibitors in cancer.
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http://dx.doi.org/10.1101/gad.270439.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719311PMC
January 2016

Financial toxicity in insured patients with multiple myeloma: a cross-sectional pilot study.

Lancet Haematol 2015 Oct 17;2(10):e408-16. Epub 2015 Sep 17.

Division of Hematology-Oncology, Division of Internal Medicine and the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.

Background: Financial toxicity is increasingly recognised as adversely affecting the quality of life and medication adherence in patients with cancer in the USA. Patients with multiple myeloma might be particularly vulnerable because of high use of novel treatments and extended treatment duration.

Methods: Between Aug 18, 2014, and Jan 7, 2015, we did a cross-sectional survey of individuals receiving at least 3 months of ongoing treatment for multiple myeloma at a tertiary academic medical centre in the USA. The survey was derived from previous reported studies and included the 11-item COST measure (financial toxicity score range 0-44). A paper survey was offered to eligible patients on arrival for routine follow-up visits, and participants were asked to complete the survey before or after their visit to the clinic. Insurance and treatment data were obtained from patients' electronic health records.

Findings: Of 111 patients approached for the study, 100 individuals completed the survey. 59 (59%) of 100 patients reported that treatment costs were higher than expected, 70 (71%) of 99 had at least minor financial burden, and 36 (36%) of 100 reported applying for financial assistance. Use of savings to pay for myeloma treatment was common (43 [46%] of 94 patients) and 21 (21%) of 98 individuals borrowed money to pay for medications. COST scores were highly correlated with patient-reported use of strategies to cope with myeloma treatment expenses. On multivariable analysis, younger age (correlation coefficient β 0·36, 95% CI 0·15 to 0·56, p=0·00092), non-married status (5·6, 1·5 to 9·6, p=0·0074), longer duration since diagnosis (-4·8, -9·3 to -0·2, p=0·042), and lower household income (US$40 000-79 999: 7·8, 2·7 to 12·9, p=0·0031; ≥$80 000: 11·8, 7·1 to 16·4, p<0·0001) were associated with higher financial burden as measured with the COST score.

Interpretation: Patient-reported financial toxicity and use of coping mechanisms were common in our insured population with multiple myeloma. Additional attention to rising treatment costs and cost sharing is needed to address the increasing evidence of financial toxicity affecting patients with cancer.

Funding: University of Pennsylvania Perelman School of Medicine.
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http://dx.doi.org/10.1016/S2352-3026(15)00151-9DOI Listing
October 2015

Bone marrow PMN-MDSCs and neutrophils are functionally similar in protection of multiple myeloma from chemotherapy.

Cancer Lett 2016 Feb 27;371(1):117-24. Epub 2015 Nov 27.

Tumor Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA; Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

Multiple myeloma (MM) is an incurable cancer of plasma cells localized preferentially in the bone marrow (BM). Resistance to chemotherapy represents one of the main challenges in MM management. BM microenvironment is known to play a critical role in protection of MM cells from chemotherapeutics; however, mechanisms responsible for this effect are largely unknown. Development of MM is associated with accumulation of myeloid-derived suppressor cells (MDSCs) mostly represented by pathologically activated relatively immature polymorphonuclear neutrophils (PMN-MDSCs). Here, we investigated whether PMN-MDSCs are responsible for BM microenvironment-mediated MM chemoresistance. Using in vivo mouse models allowing manipulation of myeloid cell number, we demonstrated a critical role for myeloid cells in MM growth and chemoresistance. PMN-MDSCs isolated from MM-bearing host are immunosuppressive and thus, functionally distinct from their counterpart in tumor-free host neutrophils. We found, however, that both PMN-MDSCs and neutrophils equally promote MM survival from doxorubicin and melphalan and that this effect is mediated by soluble factors rather than direct cell-cell contact. Our data indicate that targeting PMN-MDSCs would enhance chemotherapy efficacy in MM.
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http://dx.doi.org/10.1016/j.canlet.2015.10.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919899PMC
February 2016

Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma.

N Engl J Med 2015 Sep;373(11):1040-7

From the Division of Hematology-Oncology, Department of Medicine (A.L.G., M.V.M., D.T.V., A.D.C., B.M.W., E.A.S.), Department of Biostatistics and Epidemiology (W.-T.H.), Department of Pathology and Laboratory Medicine (S.F.L., Y.D.M., J.J.M., Z.Z., A.B., B.L.L., C.H.J.), and Abramson Cancer Center (A.L.G., M.V.M., W.-T.H., S.F.L., Y.D.M., J.J.M., Z.Z., D.T.V., A.D.C., B.M.W., K.D., N.D.S.K., A.B., B.L.L., C.H.J., E.A.S.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative chemotherapy (melphalan, 140 mg per square meter of body-surface area) and autologous stem-cell transplantation. Four years earlier, autologous transplantation with a higher melphalan dose (200 mg per square meter) had induced only a partial, transient response. Autologous transplantation followed by treatment with CTL019 cells led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein at the most recent evaluation, 12 months after treatment. This response was achieved despite the absence of CD19 expression in 99.95% of the patient's neoplastic plasma cells. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02135406.).
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http://dx.doi.org/10.1056/NEJMoa1504542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646711PMC
September 2015

NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma.

Nat Med 2015 Aug 20;21(8):914-921. Epub 2015 Jul 20.

The Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4 × 10(9) engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels. Engineered T cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, in accordance with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression-free survival of 19.1 months. NY-ESO-1-LAGE-1 TCR-engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma.
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http://dx.doi.org/10.1038/nm.3910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529359PMC
August 2015