Publications by authors named "Lawrence G Lum"

75 Publications

Priming of pancreatic cancer cells with bispecific antibody armed activated T cells sensitizes tumors for enhanced chemoresponsiveness.

Oncoimmunology 2021 Jun 1;10(1):1930883. Epub 2021 Jun 1.

Department of Medicine, Division of Hematology and Oncology, University of Virginia Cancer Center, Charlottesville, Virginia, USA.

In this study, we investigated the ability of bispecific antibody armed activated T cells to target drug resistant pancreatic cancer cells and whether or not "priming" these resistant cancer cells with bispecific antibody armed activated T cells could enhance subsequent responsiveness to chemotherapeutic drugs. Chemotherapeutic responses for pancreatic cancer are either limited or the tumors develop resistance to chemotherapy regimens. The impetus for this study was the remarkable clinical response seen in our earlier phase I/II clinical trial: a pancreatic cancer patient with drug resistant tumors who showed progression of disease following three infusions of anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) was restarted on the initial low dose of showed complete response, suggesting that BATs infusions may have sensitized patient's tumor for chemoresponsiveness. In the current study, we tested the hypothesis that BATs can sensitize tumors for chemoresponsiveness. Gemcitabine or cisplatin-resistant MiaPaCa-2 and L3.6 cell lines were effectively targeted by EGFR BATs. Priming of drug sensitive or resistant cells with EGFR BATs followed by retargeting with lower concentrations of 50% inhibitory concentration of gemcitabine or cisplatin showed enhanced cytotoxicity. Gemcitabine or cisplatin-resistant cell lines show an increased proportion of CD44/CD24/EpCAM cancer stem like cells as well as an increased number of ABC transporter ABCG2 positive cells compared to the parental cell lines. These data suggest that bispecific antibody armed activated T cells can target and kill chemo-resistant tumor cells and also markedly augment subsequent chemotherapeutic responsiveness, possibly by modulating the expression of ABC transporters.
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http://dx.doi.org/10.1080/2162402X.2021.1930883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172155PMC
June 2021

Phase II clinical trial using anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) consolidation therapy for HER2 negative (0-2+) metastatic breast cancer.

J Immunother Cancer 2021 Jun;9(6)

Medicine, University of Virginia, Charlottesville, Virginia, USA

Background: Metastatic human epidermal growth receptor II (HER2) negative breast cancer remains incurable. Our phase I study showed that anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) may be effective against HER2-tumors. This phase II trial evaluates the efficacy and immune responses of HER2 BATs given to patients with metastatic HER2-estrogen and/or progesterone receptor positive (HR+) and triple negative breast cancer (TNBC) as immune consolidation after chemotherapy. The primary objective of this study was to increase the traditional median time to progression after failure of first-line therapy of 2-4 months with the secondary endpoints of increasing overall survival (OS) and immune responses.

Methods: HER2- metastatic breast cancer (MBC) patients received 3 weekly infusions of HER2 BATs and a boost after 12 weeks.

Results: This phase II study included 24 HER2-HR+ and 8 TNBC patients who received a mean of 3.75 and 2.4 lines of prior chemotherapy, respectively. Eight of 32 evaluable patients were stable at 4 months after the first infusion. There were no dose limiting toxicities. Tumor markers decreased in 13 of 23 (56.5%) patients who had tumor markers. The median OS was 13.1 (95% CI 8.6 to 17.4), 15.2 (95% CI 8.6 to 19.8), and 12.3 (95% CI 2.1 to 17.8) months for the entire group, HER2-HR+, and TNBC patients, respectively. Median OS for patients with chemotherapy-sensitive and chemotherapy-resistant disease after chemotherapy was 14.6 (9.6-21.8) and 8.6 (3.3-17.3) months, respectively. There were statistically significant increases in interferon-γ immunospots, Th cytokines, Th cytokines, and chemokines after HER2 BATs infusions.

Conclusions: In heavily pretreated HER2-patients, immune consolidation with HER2 BATs after chemotherapy appears to increase the proportion of patients who were stable at 4 months and the median OS for both groups as well as increased adaptive and innate antitumor responses. Future studies combining HER2 BATs with checkpoint inhibitors or other immunomodulators may improve clinical outcomes.
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http://dx.doi.org/10.1136/jitc-2020-002194DOI Listing
June 2021

Potent ex vivo armed T cells using recombinant bispecific antibodies for adoptive immunotherapy with reduced cytokine release.

J Immunother Cancer 2021 May;9(5)

Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Background: T cell-based immunotherapies using chimeric antigen receptors (CAR) or bispecific antibodies (BsAb) have produced impressive responses in hematological malignancies. However, major hurdles remained, including cytokine release syndrome, neurotoxicity, on-target off-tumor effects, reliance on autologous T cells, and failure in most solid tumors. BsAb armed T cells offer a safe alternative.

Methods: We generated ex vivo armed T cells (EATs) using IgG-[L]-scFv-platformed BsAb, where the anti-CD3 (huOKT3) scFv was attached to the light chain of a tumor-binding IgG. BsAb density on EAT, in vitro cytotoxicity, cytokine release, in vivo trafficking into tumors, and their antitumor activities were evaluated in multiple cancer cell lines and patient-derived xenograft mouse models. The efficacy of EATs after cryopreservation was studied, and gamma delta (γδ) T cells were investigated as unrelated alternative effector T cells.

Results: The antitumor potency of BsAb armed T cells was substantially improved using the IgG-[L]-scFv BsAb platform. When compared with separate BsAb and T cell injection, EATs released less TNF-α, and infiltrated tumors faster, while achieving robust antitumor responses. The in vivo potency of EAT therapy depended on BsAb dose for arming, EAT cell number per injection, total number of EAT doses, and treatment schedule intensity. The antitumor efficacy of EATs was preserved following cryopreservation, and EATs using γδ T cells were safe and as effective as αβ T cell-EATs.

Conclusions: EATs exerted potent antitumor activities against a broad spectrum of human cancer targets with remarkable safety. The antitumor potency of EATs depended on BsAb dose, cell number and total dose, and schedule. EATs were equally effective after cryopreservation, and the feasibility of third-party γδ-EATs offered an alternative for autologous T cell sources.
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http://dx.doi.org/10.1136/jitc-2020-002222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126293PMC
May 2021

Arming "old guards" with "new dual-targeting weapons".

Cancer Cell 2021 May;39(5):604-606

Laboratory of Novel Biologics, Department of Biochemistry and Molecular Genetics, University of Virginia Cancer Center, Charlottesville, VA, USA. Electronic address:

The long-held paradigm that tumor suppressors are un-targetable in cancer therapy is challenged by a study published in Science. This recent work elegantly describes and characterizes a p53 mutant peptide-selective TCR-mimic antibody and its co-targeting T cell-activating bispecific antibody to eliminate neoantigen-expressing tumors.
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http://dx.doi.org/10.1016/j.ccell.2021.04.010DOI Listing
May 2021

Bispecific antibodies for the treatment of breast cancer.

Expert Opin Biol Ther 2021 May 9:1-11. Epub 2021 May 9.

Division of Hematology/Oncology, University of Virginia Charlottesville, VA, USA.

Introduction: There are more than two dozen bispecific antibodies (BsAbs) in development with a variety of designs which are relevant to breast cancer. The field of BsAbs for breast cancer includes agents that co-direct immune recognition of the cancer cell, target unique cancer antigens, and target the microenvironment. BsAbs are being developed for use as antibody-drug conjugates and as homing signals for engineered T-cells.

Areas Covered: This review covers potential targets for bispecific antibodies, agents in pre-clinical development, agents in clinical trials, combinatorial therapies, and future directions.

Expert Opinion: There is no BsAb approval expected for breast cancer in the near term, but late-stage trials are underway. Future BsAb roles in breast cancer are possible given unmet needs in estrogen receptor+ disease, residual disease, and de-escalating chemotherapy use. The HER2+ space shows hints of success for BsAbs, but is already crowded. Areas of unmet need still exist.
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http://dx.doi.org/10.1080/14712598.2021.1922665DOI Listing
May 2021

Convalescent plasma for preventing critical illness in COVID-19: A phase 2 trial and immune profile.

medRxiv 2021 Feb 19. Epub 2021 Feb 19.

Rationale: The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an unprecedented event requiring rapid adaptation to changing clinical circumstances. Convalescent immune plasma (CIP) is a promising treatment that can be mobilized rapidly in a pandemic setting.

Objectives: We tested whether administration of SARS-CoV-2 CIP at hospital admission could reduce the rate of ICU transfer or 28 day mortality.

Methods: In a single-arm phase II study, patients >18 years-old with respiratory symptoms documented with COVID-19 infection who were admitted to a non-ICU bed were administered two units of CIP within 72 hours of admission. Detection of respiratory tract SARS-CoV-2 by polymerase chain reaction and circulating anti-SARS-CoV-2 antibody titers were measured before and at time points after CIP transfusion.

Measurements And Main Results: Twenty-nine patients were transfused CIP and forty-eight contemporaneous controls were identified with comparable baseline characteristics. Levels of anti-SARS-CoV-2 IgG, IgM, and IgA anti-spike, anti-receptor-binding domain, and anti-nucleocapsid significantly increased from baseline to post-transfusion for all proteins tested. In patients transfused with CIP, the rate of ICU transfer was 13.8% compared to 27.1% for controls with a hazard ratio 0.506 (95% CI 0.165-1.554), and 28-day mortality was 6.9% compared to 10.4% for controls, hazard ratio 0.640 (95% CI 0.124-3.298).

Conclusions: Transfusion of high-titer CIP to patients early after admission with COVID-19 respiratory disease was associated with reduced ICU transfer and 28-day mortality but was not statistically significant. Follow up randomized trials may inform the use of CIP for COVID-19 or future coronavirus pandemics.
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http://dx.doi.org/10.1101/2021.02.16.21251849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899478PMC
February 2021

Granzyme B Is a Biomarker For Suspicion of Malignant Seromas Around Breast Implants.

Aesthet Surg J 2020 Nov 9. Epub 2020 Nov 9.

Background: Granzyme B (GrB) is a serine protease secreted by cytotoxic lymphocytes along with pore forming perforin to mediate apoptosis in target cells. GrB has been detected in tumor cells associated with systemic and breast implant associated anaplastic large cell lymphoma (BIA-ALCL) but its potential use for detection of early BIA-ALCL has not been fully investigated.

Objectives: With Increasing numbers of patients affected by BIA-ALCL, it becomes important to identify new biomarkers to detect early disease in malignant seromas and to better understand the nature of the neoplastic cell.

Methods: A Human XL Cytokine Discovery Magnetic Luminex 45-plex Fixed Panel Performance Assay was used to compare cytokine levels in cell culture supernates of BIA-ALCL and other T cell lymphomas, as well as malignant and benign seromas surrounding breast implants. Immunohistochemistry was employed to localize GrB to cells in seromas and capsular infiltrates.

Results: Differences in concentration of GrB between malignant and benign seromas were significant (p<0.001). GrB was found in and around apoptotic tumor cells raising the hypothesis the protease may be involved in tumor cell death.

Conclusions: GrB is a useful marker for early detection of malignant seromas and to identify tumor cells in seromas and capsular infiltrates. Because of overlap between the lowest concentrations of soluble GrB in malignant seromas with highest concentrations of GrB in benign seromas, it is recommended that GrB be used only as part of a panel of biomarkers for the screening and early detection of BIA-ALCL.
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http://dx.doi.org/10.1093/asj/sjaa302DOI Listing
November 2020

Clinical and immune responses to anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (EGFR BATs) in pancreatic cancer patients.

Oncoimmunology 2020 06 10;9(1):1773201. Epub 2020 Jun 10.

Department of Oncology, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA.

Purpose This was a phase I/II adoptive T cell trial in 7 locally advanced and metastatic pancreatic cancer patients using 3-8 infusions of anti-CD3 x anti-EGFR bispecific antibody armed activated T cells (BATs) to determine safety, the maximum tolerated dose (MTD), immune responses, time to progression (TTP), and overall survival (OS). : T cells obtained by apheresis were expanded and armed with EGFRBi, cryopreserved for infusions. In a phase I dose escalation, five patients received three weekly infusions of 10-40 × 10 BATs/infusion followed by a booster infusion 3 months later, and 2 patients received 8 infusions twice weekly for 4 weeks in a phase II. The trials were registered at http://www.clinicaltrials.gov, NCT01420874 and NCT02620865. : There were no dose-limiting toxicities (DLTs), and the targeted dose of 80 × 10 BATs was met. The median TTP is 7 months, and the median OS is 31 months. Two patients had stable disease for 6.5 and 25+ months, and two patients developed complete responses (CRs) after restarting chemotherapy. Infusions of BATs induced anti-pancreatic cancer cytotoxicity, innate immune responses, cytokine responses (IL-12, IP-10), and shifts in CD4 and CD8 Vβ repertoire with enhanced cytoplasmic IFN-γ staining in the Vβ repertoire of the CD8 subset that suggest specific clonal TCR responses. : Infusions of BATs are safe, induce endogenous adaptive anti-tumor responses, and may have a potential to improve overall survival.
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http://dx.doi.org/10.1080/2162402X.2020.1773201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480816PMC
June 2020

Anti-tumor and immune modulating activity of T cell induced tumor-targeting effectors (TITE).

Cancer Immunol Immunother 2021 Mar 31;70(3):633-656. Epub 2020 Aug 31.

Bone Marrow Transplant Program, Division of Hematology/Oncology, Department of Medicine, University of Virginia Cancer Center, 1335 Lee Street, West Complex 7191, Charlottesville, VA, 22908, USA.

Adoptive transfer of Bispecific antibody Armed activated T cells (BATs) showed promising anti-tumor activity in clinical trials in solid tumors. The cytotoxic activity of BATs occurs upon engagement with tumor cells via the bispecific antibody (BiAb) bridge, which stimulates BATs to release cytotoxic molecules, cytokines, chemokines, and other signaling molecules extracellularly. We hypothesized that the release of BATs Induced Tumor-Targeting Effectors (TITE) by this complex interaction of T cells, bispecific antibody, and tumor cells may serve as a potent anti-tumor and immune-activating immunotherapeutic approach. In a 3D tumorsphere model, TITE showed potent cytotoxic activity against multiple breast cancer cell lines compared to control conditioned media (CM): Tumor-CM (T-CM), BATs-CM (B-CM), BiAb Armed PBMC-CM (BAP-CM) or PBMC-CM (P-CM). Multiplex cytokine analysis showed high levels of Th cytokines and chemokines; phospho-protein signaling array data suggest that the prominent JAK1/STAT1 pathway may be responsible for the induction and release of Th cytokines/chemokines in TITE. In xenograft breast cancer models, IV injections of 10× concentrated TITE (3×/week for 3 weeks; 150 μl TITE/injection) was able to inhibit tumor growth significantly (ICR/scid, p < 0.003; NSG p < 0.008) compared to the control mice. We tested the key components of the TITE for immune activating and anti-tumor activity individually and in combinations, the combination of IFN-γ, TNF-α and MIP-1β recapitulates the key activities of the TITE. In summary, master mix of active components of BATs-Tumor complex-derived TITE can provide a clinically controllable cell-free platform to target various tumor types regardless of the heterogeneous nature of the tumor cells and mutational tumor.
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http://dx.doi.org/10.1007/s00262-020-02692-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914128PMC
March 2021

Enhanced cytotoxicity against solid tumors by bispecific antibody-armed CD19 CAR T cells: a proof-of-concept study.

J Cancer Res Clin Oncol 2020 Aug 24;146(8):2007-2016. Epub 2020 May 24.

Division of Hematology/Oncology, Department of Medicine, University of Virginia Cancer Center, 1335 Lee Street, West Complex 7191, Charlottesville, VA, 22908, USA.

Purpose: Although adoptive cell therapy with chimeric antigen receptor (CAR)-engineered T cells has shown durable clinical efficacy in patients with CD19 B cell malignancies, the application of this approach to solid tumors is challenging. The goal of this proof-of-concept study was to investigate whether loading of CD19-CAR T cells (CART19) with anti-HER2 or anti-EGFR bispecific antibodies (BiAb) will target HER2/EGFR CD19 targets and signal the intracellular domain of CAR without engaging antigen-specific CD19 ScFv of CAR T cells.

Methods: We used CART19 armed with anti-CD3 (OKT3) × anti-HER2 BiAb (HER2Bi) or anti-CD3 (OKT3) × anti-EGFR BiAb (EGFRBi) to evaluate the cytotoxicity directed at HER2 or EGFR expressing cancer cell lines compared with unarmed CART19 measured by short-term Cr release assay and long-term real-time cell analysis using xCelligence. We also determined the differences in exhaustion or effector phenotypes and cytokine profiles during the short- and long-term cytotoxicity assays.

Results: Specific cytotoxicity was exhibited by CART19 armed with HER2Bi or EGFRBi against multiple tumor cell lines. Armed CART19 and armed activated T cells (ATC) showed comparable specific cytotoxicity that ranged between 10 and 90% against breast, pancreatic, ovarian, prostate, and lung cancer cell lines at 10:1 E/T ratio. Serial killing (repeated killing) by HER2Bi-armed CART19 ranged between 80 and 100% at 10:1 E/T ratio against MCF-7 cells up to 19 days (up to 4th round of repeated killing) measured by a real-time cell analysis without CART19 becoming exhausted.

Conclusions: HER2Bi- or EGFRBi-armed CART19 exhibited specific cytotoxicity against multiple HER2/EGFR/CD19 tumor targets in overnight and long-term serial killing assays. CART19 showed improved survival and were resistant to exhaustion after prolonged repeated exposure to tumor cells.
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http://dx.doi.org/10.1007/s00432-020-03260-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375514PMC
August 2020

Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1 Myeloma Cells and Release Type-1 Cytokines.

Front Oncol 2020 5;10:544. Epub 2020 May 5.

Division of Hematology and Oncology, Bone Marrow Transplantation and Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, United States.

Multiple myeloma (MM) remains incurable despite advances in chemotherapy, targeted therapies, and immunotherapy. Bispecific antibody (BiAb)-armed activated T cells (BATs) have been developed for targeting and treatment of solid and hematologic malignancies. BATs are serial killers of tumor cells, secrete Th cytokines, and induce adaptive cellular and humoral immune responses in patients (pts). This study provides preclinical data using bispecific anti-CS1 (elotuzumab) × anti-CD3 (OKT3) antibody (CS1Bi)-armed activated T cells (CS1- BATs) that provide a strong rationale for applying CS1-BATs to pts with MM. CS1-BATs and unarmed activated T cells (ATC) were incubated with MM cell targets at various effector to target ratios (E:T) in a quantitative flow cytometry-based assay to determine the degree of cell loss relative to target cells incubated without ATC. ATC from up to 8 normal donors were armed with various concentrations of CS1 BiAb and tested against 5 myeloma cells lines for CS1-BATs-mediated killing and release of Th cytokines, chemokines and granzyme B. CS1-BATs from normal donors killed each of 5 MM cell lines proportional to E:T ratios ranging between 1:1 and 10:1 and arming concentrations of 12.5 to 50 ng/million ATC, which was accompanied by release of Th cytokines, chemokines and granzyme B. CS1-BATs prepared from MM pts' peripheral blood mononuclear cells (PBMC) showed increasing cytotoxicity and T cell expansion over time against ARH77 MM cells. The optimal arming dose of CS1Bi is 50 ng/10 ATC. These data demonstrate the therapeutic potential of CS1-BATs-mediated cytotoxicity and Th cytokines release at low E:T and support advancing their clinical development in pts with MM.
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http://dx.doi.org/10.3389/fonc.2020.00544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214537PMC
May 2020

Treatment of hematological malignancies with T cell redirected bispecific antibodies: current status and future needs.

Expert Opin Biol Ther 2019 07 13;19(7):707-720. Epub 2019 May 13.

a Division of Hematology/Oncology , University of Virginia , Charlottesville , VA , USA.

Introduction: Enthusiasm for developing therapeutic bispecific antibodies (BsAbs) for cancer applications has become intense in the past decade facilitated by advances in molecular biology, hybridoma technology, and protein engineering. The central strategy in BsAb engineering is to combine the specificities directed at effector cells, and at a tumor target associated antigen (TAA) into a single construct.

Areas Covered: This article highlights the clinical use of BsAbs to target effector cells to multiple myeloma (MM), non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). We discuss the successes, challenges, and future strategies. Secondary literature search was performed using Pubmed, clinicaltrials.gov and non-proprietary internet search engines.

Expert Opinion: The use of BsAb constructs to target hematologic malignancies has achieved limited success to date. There continues to be a high level of enthusiasm for developing and applying new constructs to overcome the challenges in engineering and clinical application for hematologic malignancies.
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http://dx.doi.org/10.1080/14712598.2019.1604672DOI Listing
July 2019

Immune T cells can transfer and boost anti-breast cancer immunity.

Oncoimmunology 2018;7(12):e1500672. Epub 2018 Aug 27.

Department of Medicine, Division of Hematology/Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA.

This proof-of-concept study investigates the immune effects in metastatic breast cancer (MBC) patients after "vaccination" with activated T cells (ATC) armed with anti-CD3 x anti-HER2 bispecific antibody (HER2 BATs) followed by immune consolidation with immune ATC "boost" after high dose chemotherapy (HDC) and autologous stem cell transplant (SCT). Approximately 2 weeks after completion of vaccination portion of the study, immune T cells were obtained by leukopheresis, activated and expanded and re-infused after HDC and SCT to test the hypothesis that transfer of immune unarmed ATC would accelerate reconstitution of anti-tumor activity after SCT. Eight metastatic breast cancer (MBC) patients received 8 infusions of HER2 BATs, low dose IL-2, and GM-CSF in the first part of the protocol to induce adaptive cellular and humoral responses. In the "boost" portion of the protocol, 6 of 8 patients received multiple infusions of unarmed ATC post SCT. There were no dose-limiting toxicities or delays in engraftment. Four of 6 patients tested for the immune correlative studies exhibited increases in anti-breast cancer (BrCa) cytotoxicity, antigen specific IFN-γ Elispots, anti-BrCa antibodies and increased IL-12 and Th serum cytokine levels after HER2 BATs infusions. Anti-BrCa tumor responses were seen as early as 2 weeks after SCT and persisted up to 2 years post-SCT. One out of 6 patients' rapidly progressed and showed poor immune responses and high Th cytokine levels. There was a significant correlation (p < 0.002) between time to progression (TTP) and anti-BrCa cytotoxicity by immune T cells. This is the first study to show that adoptive transfer of immune T cells after SCT accelerates reconstitution of anti-BrCa specific immunity and correlates with delay TTP.
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http://dx.doi.org/10.1080/2162402X.2018.1500672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279339PMC
August 2018

Bispecific antibody based therapeutics: Strengths and challenges.

Blood Rev 2018 07 20;32(4):339-347. Epub 2018 Feb 20.

Department of Medicine, Division of Hematology/Oncology, University of Virginia Cancer Center, Charlottesville, VA, USA.

Monoclonal antibody-based targeted therapy has greatly improved treatment options for patients. However, long-term efficacy of such antibodies is limited by resistance mechanisms. New insights into the mechanisms by which tumors evade immune control have driven innovative therapeutic strategies to eliminate cancer by re-directing immune cells to tumors. Advances in protein engineering technology have generated multiple bispecific antibody (BsAb) formats capable of targeting multiple antigens as a single agent. Approval of two BsAb and three check point blocking mAbs represent a paradigm shift in the use of antibody constructs. Since BsAbs can directly target immune cells to tumors, drug resistance and severe adverse effects are much reduced. The wave of next generation "bispecific or multispecific antibodies" has advanced multiple candidates into ongoing clinical trials. In this review, we focus on preclinical and clinical studies in hematological malignancies as well as discuss reasons for the limited success of BsAbs against solid tumors.
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http://dx.doi.org/10.1016/j.blre.2018.02.004DOI Listing
July 2018

Bispecific Antibody Armed T Cells to Target Cancer Cells.

Methods Mol Biol 2018 ;1722:117-126

Department of Neurosurgery, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.

The common strategy for making bispecific antibodies (BsAbs) involves combining the variable domains of the desired monoclonal antibodies (mAbs) into a single bispecific structure. Bispecific immunotherapeutics has generated many different formats of BsAbs including chemical heteroconjugation of two complete molecules or fragments of monoclonal antibodies, quadroma, F(ab), diabodies, tandem diabodies, and single-chain antibodies (scFv). This chapter describes the process of generating activated T cells and arming T cells with heteroconjugated BsAbs to target cancer cells.
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http://dx.doi.org/10.1007/978-1-4939-7553-2_8DOI Listing
August 2018

Immune Modulation Therapy and Imaging: Workshop Report.

J Nucl Med 2018 03 17;59(3):410-417. Epub 2017 Aug 17.

National Cancer Institute, Bethesda, Maryland.

A workshop at the National Cancer Institute on May 2, 2016, considered the current state of imaging in assessment of immunotherapy. Immunotherapy has shown some remarkable and prolonged responses in the treatment of tumors. However, responses are variable and frequently delayed, complicating the evaluation of new immunotherapy agents and customizing treatment for individual patients. Early anatomic imaging may show that a tumor has increased in size, but this could represent pseudoprogression. On the basis of imaging, clinicians must decide if they should stop, pause, or continue treatment. Other imaging technologies and approaches are being developed to improve the measurement of response in patients receiving immunotherapy. Imaging methods that are being evaluated include radiomic methods using CT, MRI, and F-FDG PET, as well as new radiolabeled small molecules, antibodies, and antibody fragments to image the tumor microenvironment, immune status, and changes over the course of therapy. Current studies of immunotherapy can take advantage of these available imaging options to explore and validate their use. Collection of CT, PET, and MR images along with outcomes from trials is critical to develop improved methods of assessment.
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http://dx.doi.org/10.2967/jnumed.117.195610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868498PMC
March 2018

Fluoroquinolone prophylaxis in autologous hematopoietic stem cell transplant recipients.

Support Care Cancer 2017 08 2;25(8):2593-2601. Epub 2017 Apr 2.

Department of Oncology, Blood and Marrow Stem Cell Transplant Program, Karmanos Cancer Institute/Wayne State University, 4100 John R, 4 HW04H0, Detroit, MI, 48201, USA.

Purpose: Although fluoroquinolone prophylaxis is frequently utilized in autologous hematopoietic stem cell transplant (AHSCT) patients, its impact on morbidity and mortality is uncertain. This study investigates the role of quinolone prophylaxis after AHSCT in recent years.

Methods: We conducted a retrospective review of 291 consecutive adult patients who underwent AHSCT for malignant disorders, between June 2013 and January 2015. Outcomes were compared between patients who received norfloxacin prophylaxis and those who did not. The endpoints were mortality during prophylaxis and at 100 days after transplant, frequency of ICU admissions, and incidence and type of bacteremia.

Results: Of 291 patients, 252 patients received norfloxacin prophylaxis and 39 patients did not. The mortality during prophylaxis and at 100 days as well as the median number of days of hospitalization following AHSCT did not differ between the two groups. No differences were noted in the frequency of ICU admission, incidence of septic shock, and duration of ICU stay. Patients who did not receive prophylaxis had a significantly higher rate of neutropenic fever (97%) than patients who received prophylaxis (77%) (p = 0.005). The patients with prophylaxis demonstrated a significantly higher rate of gram-positive bacteremia as compared to those without prophylaxis (p = 0.002). Frequency of Clostridium difficile infection was similar during and post-prophylaxis. More antibiotic use was noted among patients without prophylaxis [97%; median 9 (range, 5-24) days] compared to patients with prophylaxis [79%; median 7 (range, 3-36) days, p = 0.04].

Conclusion: Although fluoroquinolone prophylaxis reduced the incidence of neutropenic fever and antibiotic use in AHSCT, it did not alter mortality or morbidity.
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http://dx.doi.org/10.1007/s00520-017-3670-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886234PMC
August 2017

Cancer Immunology and Immunotherapy.

Anticancer Res 2016 11;36(11):5593-5606

Emily Couric Cancer Center, Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, VA, U.S.A.

Hanahan and Weinberg described six distinct biological properties of cancer cells that enable tumor growth and metastasis. These properties were referred to as the traditional hallmarks of cancer. Recent discoveries further elucidated hallmarks including evasion of immune destruction by tumor cells that disrupt anticancer response pathways. This review discusses cancer immunology and new treatment strategies aimed at restoration of antitumor immune responses.
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http://dx.doi.org/10.21873/anticanres.11144DOI Listing
November 2016

Incidence, etiology, and outcome of pleural effusions in allogeneic hematopoietic stem cell transplantation.

Am J Hematol 2016 09 14;91(9):E341-7. Epub 2016 Jul 14.

Department of Oncology, Co-Director, Blood and Marrow Stem Cell Transplant Program, Karmanos Cancer Institute/Wayne State University, Detroit, Michigan.

Pleural effusion is a known entity in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT); however, the incidence, risk factors, and morbidity-mortality outcomes associated with pleural effusions remain unknown. We retrospectively evaluated pleural effusions in 618 consecutive adult patients who underwent allogeneic HSCT from January 2008 to December 2013 at our institution. Seventy one patients developed pleural effusion at a median of 40 days (range, 1 - 869) post-HSCT with the cumulative incidence of 9.9% (95% CI, 7.7 - 12.5%) at 1 year. Infectious etiology was commonly associated with pleural effusions followed by volume overload and serositis type chronic GVHD. In multivariate analysis, higher comorbidity index (P = 0.03) and active GVHD (P = 0.018) were found to be significant independent predictors for pleural effusion development. Higher comorbidity index, very high disease risk index, ≤7/8 HLA matching, and unrelated donor were associated with inferior overall survival (OS) (P < 0.03). More importantly, patients with pleural effusion were noted to have poor OS in comparison to patients without pleural effusion (P < 0.001). Overall, pleural effusion is a frequently occurring complication after allogeneic HSCT, adding to morbidity and mortality and hence, early identification is required. Am. J. Hematol. 91:E341-E347, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajh.24435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852667PMC
September 2016

immunization by bispecific antibody targeted T cell therapy in breast cancer.

Oncoimmunology 2016 Mar 15;5(3):e1055061. Epub 2015 Jul 15.

Department of Oncology; Wayne State University, and Karmanos Cancer Institute; Detroit, MI, USA; Department of Medicine; Wayne State University, and Karmanos Cancer Institute; Detroit, MI, USA; Department of Pediatrics; Wayne State University, and Karmanos Cancer Institute; Detroit, MI, USA; Department of Immunology and Microbiology; Wayne State University and Karmanos Cancer Institute; Detroit, MI, USA.

Metastatic breast cancer remains an incurable disease. Most patients experience objective treatment responses associated with palliation of symptoms; however, progression inevitably occurs. Thus, there is an urgent need for innovative therapeutic strategies that may halt disease progression. Adoptive T-cell therapy is a potent and promising treatment option with the potential to harness the intrinsic antitumor power of the immune system and provide long-term immunity against cancer.
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http://dx.doi.org/10.1080/2162402X.2015.1055061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839366PMC
March 2016

Targeted delivery of siRNA to activated T cells via transferrin-polyethylenimine (Tf-PEI) as a potential therapy of asthma.

J Control Release 2016 05 19;229:120-129. Epub 2016 Mar 19.

Wayne State University, Detroit, MI, United States; Karmanos Cancer Institute, Detroit, MI, United States; Ludwig-Maximilians Universität München, Munich, Germany. Electronic address:

Asthma is a worldwide health problem. Activated T cells (ATCs) in the lung, particularly T helper 2 cells (Th2), are strongly associated with inducing airway inflammatory responses and chemoattraction of inflammatory cells in asthma. Small interfering RNA (siRNA) as a promising anti-sense molecule can specifically silence inflammation related genes in ATCs, however, lack of safe and efficient siRNA delivery systems limits the application of siRNA as a therapeutic molecule in asthma. Here, we designed a novel pulmonary delivery system of siRNA, transferrin-polyethylenimine (Tf-PEI), to selectively deliver siRNA to ATCs in the lung. Tf-PEI polyplexes demonstrated optimal physicochemical properties such as size, distribution, zeta-potential, and siRNA condensation efficiency. Moreover, in vitro studies showed significantly enhanced cellular uptake and gene knockdown mediated by Tf-PEI polyplexes in human primary ATCs. Biodistribution of polyplexes in a murine asthmatic model confirmed that Tf-PEI polyplexes can efficiently and selectively deliver siRNA to ATCs. In conclusion, the present work proves the feasibility to target ATCs in asthma via Tf receptor. This strategy could potentially be used to design an efficient siRNA delivery system for asthma therapy.
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http://dx.doi.org/10.1016/j.jconrel.2016.03.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886848PMC
May 2016

"NextGen" Biologics: Bispecific Antibodies and Emerging Clinical Results.

Expert Opin Biol Ther 2016 16;16(5):675-88. Epub 2016 Mar 16.

a Department of Oncology , Wayne State University and Karmanos Cancer Institute , Detroit , MI , USA.

Introduction: Bispecific antibodies (BsAb) are emerging as a novel approach for dual targeting strategies. Two bispecific antibodies are approved for therapy and >30 are in clinical development. The first generation of BsAb were produced by chemical cross-linking or hybridoma technology; with the recent advent of genetic and protein engineering technologies numerous formats of bispecific antibodies have emerged using either the fragments of IgG or whole IgG molecules. Further areas of development include dual blockade of different disease pathways, diagnosis and imaging.

Areas Covered: Biologics, including bi- or multi-specific antibodies and T cell-based approaches are rapidly changing the landscape of cancer therapeutics. New engineering platforms for bi- or multi-specific antibodies and scaffolds offer improved efficacy and reduced toxicities over IgG-based monoclonal antibodies. Preclinical and clinical studies using different formats of BsAbs are described in this review using PubMed as a literature search tool.

Expert Opinion: A comprehensive presentation of preclinical data and clinical trials evaluating the various formats of BsAbs indicate their safety and efficacy. However, a vast opportunity to fine tune physical properties and functional activity of biologics to improve the stability, engagement of cytotoxic CD8 T cells and multi-antigen targeting strategy through protein engineering holds a greater therapeutic potential.
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http://dx.doi.org/10.1517/14712598.2016.1150996DOI Listing
October 2016

Targeting CD138-/CD20+ Clonogenic Myeloma Precursor Cells Decreases These Cells and Induces Transferable Antimyeloma Immunity.

Biol Blood Marrow Transplant 2016 May 28;22(5):869-78. Epub 2016 Jan 28.

Department of Oncology, Wayne State University, Detroit, Michigan; Department of Medicine, Wayne State University, Detroit, Michigan.

This phase Ib clinical trial evaluated whether pretargeting of CD20(+) clonogenic myeloma precursor cells (CMPCs) with anti-CD3 × anti-CD20 bispecific antibody-armed T cells (BATs) before autologous stem cell transplantation (SCT) in patients with standard-risk and high-risk multiple myeloma would induce antimyeloma immunity that could be detected and boosted after SCT. All 12 patients enrolled in this study received 2 BATs infusions before SCT, and 4 patients received a booster infusion of BATs after SCT. Pretargeting CD138(-)/CD20(+) CMPCs with BATs before SCT was safe and reduced levels of CMPCs by up to 58% in the postinfusion bone marrow in patients who remained in remission. Four of 5 patients who remained in remission had a >5-fold increase in IFN-γ enzyme-linked immunospot responses. SOX2 antibody increased after BATs infusions and persisted after SCT. The median anti-SOX2 level at 3 months after SCT was 28.1 ng/mL (range, 4.6 to 256 ng/mL) in patients who relapsed and 46 ng/mL (range, 28.3 to 73.3 ng/mL) in patients who remained in remission. The immune correlates suggest that infusions of targeted T cells given before SCT were able to reduce CMPC levels and induced cellular and humoral antimyeloma immunity that could be transferred and boosted after SCT.
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http://dx.doi.org/10.1016/j.bbmt.2015.12.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820521PMC
May 2016

Preferential expression of functional IL-17R in glioma stem cells: potential role in self-renewal.

Oncotarget 2016 Feb;7(5):6121-35

Department of Neurosurgery, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA.

Gliomas are the most common primary brain tumor and one of the most lethal solid tumors. Mechanistic studies into identification of novel biomarkers are needed to develop new therapeutic strategies for this deadly disease. The objective for this study was to explore the potential direct impact of IL-17-IL-17R interaction in gliomas. Immunohistochemistry and flow cytometry analysis of 12 tumor samples obtained from patients with high grade gliomas revealed that a considerable population (2-19%) of cells in all malignant gliomas expressed IL-17RA, with remarkable co-expression of the glioma stem cell (GSC) markers CD133, Nestin, and Sox2. IL-17 enhanced the self-renewal of GSCs as determined by proliferation and Matrigel® colony assays. IL-17 also induced cytokine/chemokine (IL-6, IL-8, interferon-γ-inducible protein [IP-10], and monocyte chemoattractant protein-1 [MCP-1]) secretion in GSCs, which were differentially blocked by antibodies against IL-17R and IL-6R. Western blot analysis showed that IL-17 modulated the activity of signal transducer and activator of transcription 3 (STAT3), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), glycogen synthase kinase-3β (GSK-3β) and β-catenin in GSCs. While IL-17R-mediated secretion of IL-6 and IL-8 were significantly blocked by inhibitors of NF-κB and STAT3; NF-κB inhibitor was more potent than STAT3 inhibitor in blocking IL-17-induced MCP-1 secretion. Overall, our results suggest that IL-17-IL-17R interaction in GSCs induces an autocrine/paracrine cytokine feedback loop, which may provide an important signaling component for maintenance/self-renewal of GSCs via constitutive activation of both NF-κB and STAT3. The results also strongly implicate IL-17R as an important functional biomarker for therapeutic targeting of GSCs.
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http://dx.doi.org/10.18632/oncotarget.6847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868744PMC
February 2016

Activated T cells armed with bispecific antibodies kill tumor targets.

Curr Opin Hematol 2015 Nov;22(6):476-83

aDepartment of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, USA bDepartment of Immunology and Microbiology, Wayne State University and Barbara Ann Karmanos Cancer Center, Detroit, Michigan, USA.

Purpose Of Review: Adoptive T-cell therapy has become one of the most exciting fields of cancer therapy in the past few years. In this article, we describe a method which combines adoptive T-cell therapy with antibody therapy by arming T cells from cord blood, normal patients, and cancer patients with bispecific antibodies capable of binding to tumor-associated antigens on one side of the bispecific antibody construct and T cells on another side of the construct. This approach redirects T cells against tumor cells in a non-MHC-restricted manner.

Recent Findings: Various methods for manipulating the immune system including check-point inhibitors, chimeric antigen receptor T cells, and bispecific antibodies have shown promising activity in treating both hematological malignancies and solid tumors with excellent success. In recent studies, activated T cells armed with bispecific antibodies have shown good preclinical activity, safety, and promising efficacy in the clinical trials.

Summary: Activated T cells armed with bispecific antibodies represent a promising treatment for cancer immunotherapy.
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http://dx.doi.org/10.1097/MOH.0000000000000176DOI Listing
November 2015

BEAM Conditioning Regimen Has Higher Toxicity Compared With High-Dose Melphalan for Salvage Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2015 Sep 6;15(9):531-5. Epub 2015 Jun 6.

Department of Oncology, Wayne State University, Detroit, MI; Department of Internal Medicine, Wayne State University, Detroit, MI; Blood and Marrow Stem Cell Transplant Program, Wayne State University, Detroit, MI.

Background: Salvage autologous stem cell transplantation (ASCT) is increasingly used for eligible patients with multiple myeloma (MM) for progress after conventional chemotherapy. We recently used BEAM (BCNU, etoposide, cytarabine, and melphalan) conditioning for patients with myeloma receiving salvage ASCT whose disease progressed after a first ASCT with high-dose melphalan (HDM). We report safety and efficacy of BEAM salvage ASCT in MM in comparison with HDM-based salvage ASCT.

Patients And Methods: Between 2008 and 2013, 43 consecutive patients received salvage ASCT for MM (19 with HDM; 24 with BEAM).

Results: The BEAM group had a higher incidence of infections, intensive level of care, and fever (19 vs. 13 patients; P = .02), whereas the melphalan group had a higher incidence of mucositis (7 vs. 2 patients; P = .03). Other toxicities were not different. There was no significant difference in disease status and response rate before and after salvage ASCT between the 2 groups. The median time of follow-up after salvage ASCT was 5 and 9 months and the median progression-free survival (PFS) times were 7.7 and 12.1 months (P = .82) for BEAM and melphalan, respectively.

Conclusion: BEAM seemed to be associated with higher toxicity with comparable efficacy to HDM ASCT. Longer follow-up is needed to determine whether there is any significant difference in PFS between the 2 groups.
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http://dx.doi.org/10.1016/j.clml.2015.05.008DOI Listing
September 2015

Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients.

Prostate Cancer 2015 23;2015:285193. Epub 2015 Feb 23.

Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA ; Department of Medicine, Wayne State University, Detroit, MI 48201, USA ; Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201, USA.

Background. New nontoxic targeted approaches are needed for patients with castrate resistant prostate cancer (CRPC). Our preclinical studies show that activated T cells (ATC) armed with anti-CD3 x anti-Her2 bispecific antibody (Her2Bi) kill prostate cancer cells lines, induce a Th1 cytokine pattern upon engagement of tumor cells, prevent the development of prostate tumors, and retard tumor growth in immunodeficient mice. These studies provided strong rationale for our phase I dose-escalation pilot study to test ATC armed with Her2Bi (aATC) for safety in men with CRPC. Methods. Seven of 8 men with CRPC were evaluable after receiving two infusions per week for 4 weeks. The men received 2.5, 5 or 10 × 10(9) aATC per infusion with low dose interleukin-2 and granulocyte-macrophage colony stimulating factor. Results. There were no dose limiting toxicities, and there was 1 partial responder and 3 of 7 patients had significant decreases in their PSA levels and pain scores. Immune evaluations of peripheral blood mononuclear cells in 2 patients before and after immunotherapy showed increases in IFN-γ EliSpot responses and Th1 serum cytokines. Conclusions. These results provide a strong rationale for developing phase II trials to determine whether aATC are effective for treating CRPC.
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http://dx.doi.org/10.1155/2015/285193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352947PMC
March 2015

Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial.

Clin Cancer Res 2015 May 16;21(10):2305-14. Epub 2015 Feb 16.

Division of Hematology and Oncology, Department of Medicine, Roger Williams Hospital, Providence, Rhode Island.

Purpose: This study reports a phase I immunotherapy trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 × anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3-activated T cells (ATC) in combination with low-dose IL-2 and granulocyte-macrophage colony-stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T-cell trafficking, immune responses, time to progression, and overall survival (OS).

Experimental Design: ATC were expanded from leukapheresis product using IL2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 × 10(9) armed ATC (aATC) per infusion.

Results: There were no dose-limiting toxicities and the MTD was not defined. It was technically feasible to grow 160 × 10(9) ATC from a single leukapheresis. aATC persisted in the blood for weeks and trafficked to tumors. Infusions of aATC induced anti-breast cancer responses and increases in immunokines. At 14.5 weeks after enrollment, 13 of 22 (59.1%) evaluable patients had stable disease and 9 of 22 (40.9%) had progressive disease. The median OS was 36.2 months for all patients, 57.4 months for HER2 3+ patients, and 27.4 months for HER2 0-2+ patients.

Conclusions: Targeting HER2(+) and HER2(-) tumors with aATC infusions induced antitumor responses, increases in Th1 cytokines, and IL12 serum levels that suggest that aATC infusions vaccinated patients against their own tumors. These results provide a strong rationale for conducting phase II trials.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433762PMC
May 2015

Targeted cancer immunotherapy via combination of designer bispecific antibody and novel gene-engineered T cells.

J Transl Med 2014 Dec 13;12:347. Epub 2014 Dec 13.

Department of Pathology and Laboratory Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Bldg 421, Smilow CTR, Rm 08-103, Philadelphia, PA, 19104-5156, USA.

Background: Redirection of T lymphocytes against tumor antigens can induce dramatic regression of advanced stage malignancy. The use of bispecific antibodies (BsAbs) that bind both the T-cell receptor (TCR) and a target antigen is one promising approach to T-cell redirection. However, BsAbs indiscriminately bind all CD3+ T-cells and trigger TCR activation in the absence of parallel costimulatory signals required to overcome T-cell unresponsiveness or anergy.

Methods: To address these limitations, a combination platform was designed wherein a unique BsAb referred to as frBsAb exclusively engages T-cells engineered to express a novel chimeric receptor comprised of extracellular folate receptor fused to intracellular TCR and CD28 costimulatory signaling domains in tandem; a BsAb-binding immune receptor (BsAb-IR). As a surrogate TCR, the BsAb-IR allows for concomitant TCR and costimulatory signaling exclusively in transduced T-cells upon engagement with specific frBsAbs, and can therefore redirect T-cells on command to desired antigen. Human primary T-cells were transduced with lentiviral vector and expanded for 14-18 days. BsAb-IRs were harvested and armed with frBsAbs to test for redirected cytotoxicity against CD20 positive cancer cell lines.

Results: Using frBsAbs specific for CD20 or HER2, the lytic activity of primary human T-cells expressing the BsAb-IR was specifically redirected against CD20+ leukemic cells or HER2+ epithelial cancer cells, respectively, while non-engineered T-cells were not activated. Notably, elimination of the CD28 costimulatory domain from the BsAb-IR construct significantly reduced frBsAb-redirected antitumor responses, confirming that frBsAbs are capable of delivering simultaneous TCR activation and costimulatory signals to BsAb-IR T-cells.

Conclusion: In summary, our results establish the proof of concept that the combination of BsAbs with optimized gene-engineered T-cells provides the opportunity to specify and augment tumor antigen-specific T-cell activation and may improve upon the early success of conventional BsAbs in cancer immunotherapy.
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http://dx.doi.org/10.1186/s12967-014-0347-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272781PMC
December 2014

Incidence, risk factors, and outcome of cytomegalovirus viremia and gastroenteritis in patients with gastrointestinal graft-versus-host disease.

Biol Blood Marrow Transplant 2015 Jan 16;21(1):159-64. Epub 2014 Oct 16.

Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.

Gastrointestinal (GI) graft-versus-host disease (GVHD) is one of the most common causes of morbidity and mortality after allogeneic stem cell transplantation. In addition, cytomegalovirus (CMV) infection of the gastrointestinal tract can complicate the post-transplantation course of these patients and it can be difficult to differentiate the 2 diagnoses given that they can present with similar symptoms. We retrospectively analyzed 252 patients who were diagnosed with GI GVHD to evaluate the incidence, risk factors, and outcomes of CMV viremia and CMV gastroenteritis in these patients. The median age at the time of transplantation was 51 years, 35% were related donor transplantations, and 65% were unrelated donor transplantations. A total of 114 (45%) patients developed CMV viremia at a median of 34 days (range, 14 to 236 days) after transplantation. Only recipient CMV IgG serostatus was significantly associated with development of CMV viremia (P < .001). The incidence of CMV viremia with relation to donor (D) and recipient (R) CMV serostatus subgroups was as follows: D+/R+, 73%; D-/R+, 67%; D+/R-, 19%; and D-/R-, 0. A total of 31 patients were diagnosed with a biopsy-proven CMV gastroenteritis; 2 patients had evidence of CMV gastroenteritis and GVHD on the first biopsy and 29 on the second biopsy. Median time to development of CMV gastroenteritis was 52 days (range, 19 to 236 days) after transplantation. Using death as a competing risk, the cumulative incidence of CMV gastroenteritis at 1 year was 16.4%. The incidence of CMV gastroenteritis in relation to the donor/recipient serostatus was as follows: D+/R+, 22%; D-/R+, 31%; D+/R-, 12%; and D-/R-, 0. Median follow-up time for the 252 patients was 35.4 (95% CI 23.8 to 44.8) months. The estimated overall survival rate at 1 and 2 years was .45 (95% confidence interval [CI], .39 to .52) and .39 (95% CI, .33 to .46), respectively. Of the examined variables, those related to the overall survival were maximal clinical GVHD grade (P < .001) and development of CMV gastroenteritis (P = .008). Development of CMV viremia was not associated with increased mortality. In conclusion, CMV gastroenteritis is common complication in patients with GI GVHD and can adversely affect the prognosis.
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http://dx.doi.org/10.1016/j.bbmt.2014.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4283200PMC
January 2015