Journal Articles

Detecting Tumor Antigen-Specific T Cells via Interaction-Dependent Fucosyl-Biotinylation

Spotlight 

Using cell-attached fucosyltransferase and a biotinylated (Bio+) substrate, Liu, Li, and Chen et al. developed FucoID, a proximity-labeling approach to specifically identify T cells binding to cognate antigen-presenting cells, allowing efficient capture of tumor antigen-specific TILs from multiple murine tumor models. The Bio+-enriched CD8+ T cells were PD-1+, possessed an exhaustion phenotype and a minor population of TCF1+ progenitor exhausted cells, and were more effective in tumor control than ‘bystander’ PD-1+ non-captured cells. Bio+-labeled CD4+ T cells contained target-reactive cells and a CD8+ T cell-suppressing (CD25+; presumably Treg) subpopulation.

Contributed by Ed Fritsch

Using cell-attached fucosyltransferase and a biotinylated (Bio+) substrate, Liu, Li, and Chen et al. developed FucoID, a proximity-labeling approach to specifically identify T cells binding to cognate antigen-presenting cells, allowing efficient capture of tumor antigen-specific TILs from multiple murine tumor models. The Bio+-enriched CD8+ T cells were PD-1+, possessed an exhaustion phenotype and a minor population of TCF1+ progenitor exhausted cells, and were more effective in tumor control than ‘bystander’ PD-1+ non-captured cells. Bio+-labeled CD4+ T cells contained target-reactive cells and a CD8+ T cell-suppressing (CD25+; presumably Treg) subpopulation.

Contributed by Ed Fritsch

ABSTRACT: Re-activation and clonal expansion of tumor-specific antigen (TSA)-reactive T cells are critical to the success of checkpoint blockade and adoptive transfer of tumor-infiltrating lymphocyte (TIL)-based therapies. There are no reliable markers to specifically identify the repertoire of TSA-reactive T cells due to their heterogeneous composition. We introduce FucoID as a general platform to detect endogenous antigen-specific T cells for studying their biology. Through this interaction-dependent labeling approach, intratumoral TSA-reactive CD4+, CD8+ T cells, and TSA-suppressive CD4+ T cells can be detected and separated from bystander T cells based on their cell-surface enzymatic fucosyl-biotinylation. Compared to bystander TILs, TSA-reactive TILs possess a distinct T cell receptor (TCR) repertoire and unique gene features. Although exhibiting a dysfunctional phenotype, TSA-reactive CD8+ TILs possess substantial capabilities of proliferation and tumor-specific killing. Featuring genetic manipulation-free procedures and a quick turnover cycle, FucoID should have the potential of accelerating the pace of personalized cancer treatment.

Author Info: (1) Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. (2) Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92

Author Info: (1) Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. (2) Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China. Electronic address: jieli@nju.edu.cn. (3) Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China. (4) Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China. (5) Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA. (6) Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: pengwu@scripps.edu.

Single-cell derived tumor organoids display diversity in HLA class I peptide presentation

Tumor heterogeneity is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug-resistant cells, where tumor-specific human leukocyte antigen (HLA) peptide ligands are promising leads to invoke targeted anti-tumor responses. Here, we investigate the variability in HLA class I peptide presentation between different clonal cells of the same colorectal cancer patient, using an organoid system. While clone-specific differences in HLA peptide presentation were observed, broad inter-clone variability was even more prevalent (15-25%). By coupling organoid proteomics and HLA peptide ligandomics, we also found that tumor-specific ligands from DNA damage control and tumor suppressor source proteins were prominently presented by tumor cells, coinciding likely with the silencing of such cytoprotective functions. Collectively, these data illustrate the heterogeneous HLA peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.

Author Info: (1) Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584

Author Info: (1) Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. Netherlands Proteomics Centre, Padualaan 8, 3584 CH, Utrecht, The Netherlands. (2) Oncode Institute, Hubrecht Institute, 3584 CT, Utrecht, The Netherlands. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, 3584 CT, Utrecht, The Netherlands. (3) Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands. (4) Oncode Institute, Hubrecht Institute, 3584 CT, Utrecht, The Netherlands. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, 3584 CT, Utrecht, The Netherlands. (5) Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. Netherlands Proteomics Centre, Padualaan 8, 3584 CH, Utrecht, The Netherlands. (6) Oncode Institute, Hubrecht Institute, 3584 CT, Utrecht, The Netherlands. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, 3584 CT, Utrecht, The Netherlands. (7) Oncode Institute, Hubrecht Institute, 3584 CT, Utrecht, The Netherlands. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, 3584 CT, Utrecht, The Netherlands. (8) Department of Pathology, St. Antonius Hospital, 3543 AZ, Utrecht, The Netherlands. (9) Department of Surgery, Diakonessenhuis Hospital, 3582 KE, Utrecht, The Netherlands. (10) Department of Surgery, Diakonessenhuis Hospital, 3582 KE, Utrecht, The Netherlands. (11) Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands. Hartwig Medical Foundation, 1098 XH, Amsterdam, The Netherlands. (12) Oncode Institute, Hubrecht Institute, 3584 CT, Utrecht, The Netherlands. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Centre Utrecht, 3584 CT, Utrecht, The Netherlands. Princess M‡xima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands. (13) Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. a.j.r.heck@uu.nl. Netherlands Proteomics Centre, Padualaan 8, 3584 CH, Utrecht, The Netherlands. a.j.r.heck@uu.nl. (14) Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands. w.wu1@uu.nl. Netherlands Proteomics Centre, Padualaan 8, 3584 CH, Utrecht, The Netherlands. w.wu1@uu.nl.

In vivo vaccination with cell line-derived whole tumor lysates: neoantigen quality, not quantity matters

BACKGROUND: Cancer vaccines provide a complex source of neoantigens. Still, increasing evidence reveals that the neoantigen quality rather than the quantity is predictive for treatment outcome. METHODS: Using the preclinical Mlh1(-/-) tumor model, we performed a side-by side comparison of two autologous cell-line derived tumor lysates (namely 328 and A7450 T1 M1) harboring different tumor mutational burden (TMB; i.e. ultra-high: 328; moderate-high: A7450 T1 M1). Mice received repetitive prophylactic or therapeutic applications of the vaccine. Tumor incidence, immune responses and tumor microenvironment was examined. RESULTS: Both tumor cell lysates delayed tumor formation in the prophylactic setting, with the A7450 T1 M1 lysate being more effective in decelerating tumor growth than the 328 lysate (median overall survival: 37 vs. 25 weeks). Comparable results were achieved in therapeutic setting and could be traced back to antigen-driven immune stimulation. Reactive T cells isolated from A7450 T1 M1-treated mice recognized autologous Mlh1(-/-) tumor cells in IFN_ ELISpot, but likewise YAC-1 cells, indicative for stimulation of both arms of the immune system. By deciphering local effects, vaccines shaped the tumor microenvironment differently. While A7450 T1 M1 prophylactically vaccinated tumors harbored low numbers of myeloid-derived suppressor cells (MDSC) and elevated CD8-T cell infiltrates, vaccination with the 328 lysate evoked MDSC infiltration. Similar effects were seen in the therapeutic setting with stable disease induction only upon A7450 T1 M1 vaccination. Untangling individual response profiles revealed strong infiltration with LAG3(+) and PD-L1(+) immune cells when treatments failed, but almost complete exclusion of checkpoint-expressing lymphocytes in long-term survivors. CONCLUSIONS: By applying two tumor cell lysates we demonstrate that neoantigen quality outranks quantity. This should be considered prior to designing cancer vaccine-based combination approaches.

Author Info: (1) Department of Medicine, Clinic III-Hematology, Oncology, Palliative Care, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany. (2) Institute for

Author Info: (1) Department of Medicine, Clinic III-Hematology, Oncology, Palliative Care, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany. (2) Institute for Biostatistics and Informatics in Medicine and Ageing Research (IBIMA), Rostock University Medical Center, University of Rostock, 18057, Rostock, Germany. Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany. Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. (3) Department of Medicine, Clinic III-Hematology, Oncology, Palliative Care, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany. (4) Department of Medicine, Clinic III-Hematology, Oncology, Palliative Care, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany. (5) Department of Cell Biology, Rostock University Medical Center, 18057, Rostock, Germany. (6) Department of Medicine, Clinic III-Hematology, Oncology, Palliative Care, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany. (7) Department of Medicine, Clinic III-Hematology, Oncology, Palliative Care, Rostock University Medical Center, Ernst-Heydemann-Str. 6, 18057, Rostock, Germany. claudia.maletzki@med.uni-rostock.de.

Adoptive immunotherapy with CB following chemotherapy for patients with refractory myeloid malignancy: chimerism and response

We conducted a prospective evaluation of cord blood (CB)-derived adoptive cell therapy, after salvage chemotherapy, for patients with advanced myeloid malignancies and poor prognosis. Previously, we reported safety, feasibility, and preliminary efficacy of this approach. We present updated results in 31 patients who received intensive chemotherapy followed by CB infusion and identify predictors of response. To enhance the antileukemic effect, we selected CB units (CBU) with shared inherited paternal antigens and/or noninherited maternal antigens with the recipients. Twenty-eight patients with acute myeloid leukemia (AML), 2 with myelodysplastic syndrome, and 1 in chronic myeloid leukemia myeloid blast crisis were enrolled; 9 had relapsed after allogeneic transplant. Response was defined as <5% blasts in hypocellular bone marrow at 2 weeks after treatment. Thirteen patients (42%) responded; a rate higher than historical data with chemotherapy only. Twelve had CBU-derived chimerism detected; chimerism was a powerful predictor of response (P < .001). CBU lymphocyte content and a prior transplant were associated with chimerism (P < .01). Safety was acceptable: 3 patients developed mild cytokine release syndrome, 2 had grade 1 and 2 had grade 4 graft-versus-host disease. Seven responders and 6 nonresponders (after additional therapy) received subsequent transplant; 5 are alive (follow-up, 5-47 months). The most common cause of death for nonresponders was disease progression, whereas for responders it was infection. CB-derived adoptive cell therapy is feasible and efficacious for refractory AML. Banked CBU are readily available for treatment. Response depends on chimerism, highlighting the graft-versus-leukemia effect of CB cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02508324.

Author Info: (1) Division of Hematology/Oncology and. Division of Pathology, Department of Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY. (2) National Cord Bloo

Author Info: (1) Division of Hematology/Oncology and. Division of Pathology, Department of Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY. (2) National Cord Blood Program, New York Blood Center, New York, NY; and. Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center, New York, NY. (3) National Cord Blood Program, New York Blood Center, New York, NY; and. (4) National Cord Blood Program, New York Blood Center, New York, NY; and. (5) Division of Pathology, Department of Medicine, Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY. (6) Division of Hematology/Oncology and. (7) National Cord Blood Program, New York Blood Center, New York, NY; and. (8) Division of Hematology/Oncology and. (9) Division of Hematology/Oncology and. (10) Division of Hematology/Oncology and. (11) Division of Hematology/Oncology and. (12) Division of Hematology/Oncology and. (13) Division of Hematology/Oncology and. (14) Division of Hematology/Oncology and. (15) Division of Hematology/Oncology and. (16) Division of Hematology/Oncology and. (17) National Cord Blood Program, New York Blood Center, New York, NY; and. (18) Division of Hematology/Oncology and. (19) Division of Hematology/Oncology and. (20) Division of Hematology/Oncology and.

Studying immunotherapy resistance in a melanoma autologous humanized mouse xenograft

Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPCs) and tumors from two melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated from cord blood-derived HSPCs and tumors from different donors, the aHM recapitulates a patient-specific tumor microenvironment (TME). When patient tumors were implanted on aHM, mHM and NOD/SCID/IL2rg-/- (NSG) cohorts, tumors appeared earlier and grew faster on NSG and mHM cohorts. We observed that immune cells differentiating in the aHM were relatively more capable of circulating peripherally, invading into tumors and interacting with the TME. A heterologous, human leukocyte antigen (HLA-A) matched cohort also yielded slower growing tumors than non-HLA-matched mHM, indicating that a less permissive immune environment inhibits tumor progression. When the aHM, mHM, and NSG cohorts were treated with immunotherapies mirroring what the originating patients received, tumor growth in the aHM accelerated, similar to the progression observed in the patients. This rapid growth was associated with decreased immune cell infiltration, reduced interferon gamma (IFN_)-related gene expression, and a reduction in STAT3 phosphorylation, events that were replicated in vitro using tumor-derived cell lines. Implications: Engrafted adult HSPCs give rise to more tumor infiltrative immune cells, increased HLA matching leads to slower tumor initiation and growth, and continuing immunotherapy past progression can paradoxically lead to increased growth.

Author Info: (1) Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus. (2) Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus. (3) Medical Oncology,

Author Info: (1) Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus. (2) Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus. (3) Medical Oncology, University of Colorado Anschutz Medical Campus. (4) Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus. (5) Medical Oncology, University of Colorado Denver Anschutz Medical Campus. (6) Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus. (7) Medical Oncology, University of Colorado School of Medicine. (8) Medical Oncology, University of Colorado Anschutz Medical Campus. (9) Medical Oncology, University of Colorado Denver Anschutz Medical Campus. (10) Medical Oncology, University of Colorado Denver Anschutz Medical Campus. (11) Medical Oncology, University of Colorado, Denver, Anschutz Medical Campus. (12) Pediatrics, University of Colorado Denver-Anschutz Medical Center. (13) Department of Biostatistics and Bioinformatics, Moffitt Cancer Center. (14) Pathology, University of Colorado School of Medicine. (15) Division of Medical Oncology, University of Colorado Anschutz Medical Campus. (16) Pathology, University of Colorado Denver. (17) Immunology and Microbiology, University of Colorado Anschutz Medical Campus. (18) Division of Medical Oncology, University of Colorado Anschutz Medical Campus and University of Colorado Cancer Center. (19) Dermatology, UNIVERSITY OF COLORADO ANSCHUTZ MEDICAL C. (20) Department of Medicine, University of Colorado Denver. (21) University of Colorado at Denver, Anschutz Medical Campus antonio.jimeno@ucdenver.edu.

Healthy Donors Harbor Memory T Cell Responses to RAS Neo-Antigens

The RAS mutations are the most frequently occurring somatic mutations in humans, and several studies have established that T cells from patients with RAS-mutant cancer recognize and kill RAS-mutant cells. Enhancing the T cell response via therapeutic cancer vaccination against mutant RAS results in a clinical benefit to patients; thus, T cells specific to RAS mutations are effective at battling cancer. As the theory of cancer immuno-editing indicates that healthy donors may clear malignantly transformed cells via immune-mediated killing, and since T cells have been shown to recognize RAS-mutant cancer cells, we investigated whether healthy donors harbor T-cell responses specific to mutant RAS. We identified strong and frequent responses against several epitopes derived from the RAS codon 12 and codon 13 mutations. Some healthy donors demonstrated a response to several mutant epitopes, and some, but not all, exhibited cross-reactivity to the wild-type RAS epitope. In addition, several T cell responses were identified against mutant RAS epitopes in healthy donors directly ex vivo. Clones against mutant RAS epitopes were established from healthy donors, and several of these clones did not cross-react with the wild-type epitope. Finally, CD45RO(+) memory T cells from healthy donors demonstrated a strong response to several mutant RAS epitopes. Taken together, these data suggest that the immune system in healthy donors spontaneously clears malignantly transformed RAS-mutant cells, and the immune system consequently generates T-cell memory against the mutations.

Author Info: (1) National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, DK-2730 Herlev, Denmark. (2) National Center for Cancer Immune Therapy, Department of Oncolo

Author Info: (1) National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, DK-2730 Herlev, Denmark. (2) National Center for Cancer Immune Therapy, Department of Oncology, Herlev Hospital, DK-2730 Herlev, Denmark. Institute for Immunology and Microbiology, Copenhagen University, DK-2200 Copenhagen, Denmark.

Fc-Engineered Antibodies with Enhanced Fc-Effector Function for the Treatment of B-Cell Malignancies

Monoclonal antibody (mAb) therapy has rapidly changed the field of cancer therapy. In 1997, the CD20-targeting mAb rituximab was the first mAb to be approved by the U.S. Food and Drug Administration (FDA) for treatment of cancer. Within two decades, dozens of mAbs entered the clinic for treatment of several hematological cancers and solid tumors, and numerous more are under clinical investigation. The success of mAbs as cancer therapeutics lies in their ability to induce various cytotoxic machineries against specific targets. These cytotoxic machineries include antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), which are all mediated via the fragment crystallizable (Fc) domain of mAbs. In this review article, we will outline the novel approaches of engineering these Fc domains of mAbs to enhance their Fc-effector function and thereby their anti-tumor potency, with specific focus to summarize their (pre-) clinical status for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL), B-cell non-Hodgkin lymphoma (B-NHL), and multiple myeloma (MM).

Author Info: (1) Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, VU Medical Center, 1081 HV Amsterdam, The Netherlands. (2) Department of Hematology, Cancer Center Amsterdam,

Author Info: (1) Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, VU Medical Center, 1081 HV Amsterdam, The Netherlands. (2) Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, VU Medical Center, 1081 HV Amsterdam, The Netherlands. (3) Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, VU Medical Center, 1081 HV Amsterdam, The Netherlands. (4) Department of Hematology, Cancer Center Amsterdam, Amsterdam UMC, VU Medical Center, 1081 HV Amsterdam, The Netherlands.

IFN-Alpha-Mediated Differentiation of Dendritic Cells for Cancer Immunotherapy: Advances and Perspectives

The past decade has seen tremendous developments in novel cancer therapies through targeting immune-checkpoint molecules. However, since increasing the presentation of tumor antigens remains one of the major issues for eliciting a strong antitumor immune response, dendritic cells (DC) still hold a great potential for the development of cancer immunotherapy. A considerable body of evidence clearly demonstrates the importance of the interactions of type I IFN with the immune system for the generation of a durable antitumor response through its effects on DC. Actually, highly active DC can be rapidly generated from blood monocytes in vitro in the presence of IFN-_ (IFN-DC), suitable for therapeutic vaccination of cancer patients. Here we review how type I IFN can promote the ex vivo differentiation of human DC and orientate DC functions towards the priming and expansion of protective antitumor immune responses. New epigenetic elements of control on activation of the type I IFN signal will be highlighted. We also review a few clinical trials exploiting IFN-DC in cancer vaccination and discuss how IFN-DC could be exploited for the design of effective strategies of cancer immunotherapy as a monotherapy or in combination with immune-checkpoint inhibitors or immunomodulatory drugs.

Author Info: (1) Department of Oncology and Molecular Medicine, Istituto Superiore di Sanitˆ, Viale Regina Elena 299, 00161 Rome, Italy. (2) Department of Oncology and Molecular Medicine, Istit

Author Info: (1) Department of Oncology and Molecular Medicine, Istituto Superiore di Sanitˆ, Viale Regina Elena 299, 00161 Rome, Italy. (2) Department of Oncology and Molecular Medicine, Istituto Superiore di Sanitˆ, Viale Regina Elena 299, 00161 Rome, Italy. (3) Department of Oncology and Molecular Medicine, Istituto Superiore di Sanitˆ, Viale Regina Elena 299, 00161 Rome, Italy.

Molecular basis and therapeutic implications of CD40/CD40L immune checkpoint

The CD40 receptor and its ligand CD40L is one of the most critical molecular pairs of the stimulatory immune checkpoints. Both CD40 and CD40 L have a membrane form and a soluble form generated by proteolytic cleavage or alternative splicing. CD40 and CD40L are widely expressed in various types of cells, among which B cells and myeloid cells constitutively express high levels of CD40, and T cells and platelets express high levels of CD40L upon activation. CD40L self-assembles into functional trimers which induce CD40 trimerization and downstream signaling. The canonical CD40/CD40L signaling is mediated by recruitment of TRAFs and NF-_B activation, which is supplemented by signal pathways such as PI3K/AKT, MAPKs and JAK3/STATs. CD40/CD40L immune checkpoint leads to activation of both innate and adaptive immune cells via two-way signaling. CD40/CD40L interaction also participates in regulating thrombosis, tissue inflammation, hematopoiesis and tumor cell fate. Because of its essential role in immune activation, CD40/CD40L interaction has been regarded as an attractive immunotherapy target. In recent years, significant advance has been made in CD40/CD40L-targeted therapy. Various types of agents, including agonistic/antagonistic monoclonal antibodies, cellular vaccines, adenoviral vectors and protein antagonist, have been developed and evaluated in early-stage clinical trials for treating malignancies, autoimmune diseases and allograft rejection. In general, these agents have demonstrated favorable safety and some of them show promising clinical efficacy. The mechanisms of benefits include immune cell activation and tumor cell lysis/apoptosis in malignancies, or immune cell inactivation in autoimmune diseases and allograft rejection. This review provides a comprehensive overview of the structure, processing, cellular expression pattern, signaling and effector function of CD40/CD40L checkpoint molecules. In addition, we summarize the progress, targeted diseases and outcomes of current ongoing and completed clinical trials of CD40/CD40L-targeted therapy.

Author Info: (1) Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Center for Metabolic Disease Research, Lewis Katz

Author Info: (1) Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA. (2) Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (3) Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA. (4) Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Cardiovascular Medicine, the First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. (5) Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA. (6) Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA; Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA. Electronic address: hong.wang@temple.edu.

Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape

We report here a combined anti-cancer therapy directed toward HER2 and EpCAM, common tumor-associated antigens of breast cancer cells. The combined therapeutic effect is achieved owing to two highly toxic proteins-a low immunogenic variant of Pseudomonas aeruginosa exotoxin A and ribonuclease Barnase from Bacillus amyloliquefaciens. The delivery of toxins to cancer cells was carried out by targeting designed ankyrin repeat proteins (DARPins). We have shown that both target agents efficiently accumulate in the tumor. Simultaneous treatment of breast carcinoma-bearing mice with anti-EpCAM fusion toxin based on LoPE and HER2-specific liposomes loaded with Barnase leads to concurrent elimination of primary tumor and metastases. Monotherapy with anti-HER2- or anti-EpCAM-toxins did not produce a comparable effect on metastases. The proposed approach can be considered as a promising strategy for significant improvement of cancer therapy.

Author Info: (1) Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, 117997 Moscow, Russia. (2) Shemyakin-Ovchinnikov Institute

Author Info: (1) Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, 117997 Moscow, Russia. (2) Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, 117997 Moscow, Russia. (3) Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, 117997 Moscow, Russia. (4) Prokhorov General Physics Institute, Russian Academy of Sciences, Vavilova Street 38, 119991 Moscow, Russia. (5) National Research Center "Kurchatov Institute", Akademika Kurchatova pl. 1, 123182 Moscow, Russia. Shubnikov Institute of Crystallography of Federal Scientific Research Centre 'Crystallography and Photonics' of Russian Academy of Sciences, Leninskiy Prospect, 59, 119333 Moscow, Russia. Moscow Institute of Physics and Technology, Institutsky Lane 9, Dolgoprudny, 141701 Moscow, Russia. (6) National Research Center "Kurchatov Institute", Akademika Kurchatova pl. 1, 123182 Moscow, Russia. Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre "Kurchatov Institute", Orlova Roscha 1, 188300 Gatchina, Russia. Peter the Great St. Petersburg Polytechnic University, Politehnicheskaya 29, 195251 St. Petersburg, Russia. (7) Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, 117997 Moscow, Russia. (8) Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, 117997 Moscow, Russia. (9) Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, 117997 Moscow, Russia. (10) Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street 16/10, 117997 Moscow, Russia. The Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, 119991 Moscow, Russia. Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia.

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