Journal Articles

CD8+ T cell states in human cancer: insights from single-cell analysis

The T cell infiltrates that are formed in human cancers are a modifier of natural disease progression and also determine the probability of clinical response to cancer immunotherapies. Recent technological advances that allow the single-cell analysis of phenotypic and transcriptional states have revealed a vast heterogeneity of intratumoural T cell states, both within and between patients, and the observation of this heterogeneity makes it critical to understand the relationship between individual T cell states and therapy response. This Review covers our current knowledge of the T cell states that are present in human tumours and the role that different T cell populations have been hypothesized to play within the tumour microenvironment, with a particular focus on CD8(+) T cells. The three key models that are discussed herein are as follows: (1) the dysfunction of T cells in human cancer is associated with a change in T cell functionality rather than inactivity; (2) antigen recognition in the tumour microenvironment is an important driver of T cell dysfunctionality and the presence of dysfunctional T cells can hence be used as a proxy for the presence of a tumour-reactive T cell compartment; (3) a less dysfunctional population of tumour-reactive T cells may be required to drive a durable response to T cell immune checkpoint blockade.

Author Info: (1) Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands. (2) Division of Molecular Oncology and Immunology, Oncode

Author Info: (1) Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands. (2) Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands. (3) Division of Molecular Oncology and Immunology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, Netherlands. t.schumacher@nki.nl.

EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma

PURPOSE: To assess the safety/tolerability and antitumor activity of enfortumab vedotin (EV), a novel investigational antibody-drug conjugate that delivers the microtubule-disrupting agent, monomethyl auristatin E, to cells that express Nectin-4. METHODS: EV-101 is a phase I dose escalation/expansion study that enrolled patients with Nectin-4-expressing solid tumors (eg, metastatic urothelial carcinoma [mUC]) who progressed on >/= 1 prior chemotherapy regimen and/or programmed death-1 receptor/programmed death ligand-1 [PD-(L)1] inhibitor, including a cohort of patients with mUC who received prior anti-PD-(L)1 therapy. Patients received escalating doses of EV up to 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Primary objectives were evaluation of safety/tolerability and pharmacokinetics; antitumor activity was a secondary objective. RESULTS: Enrolled patients with mUC (n = 155) were heavily pretreated, with 96% having prior platinum-based chemotherapy and 29% receiving >/= 3 lines of prior treatment. Maximum tolerated dose of EV was not established; however, the recommended phase II dose was identified as 1.25 mg/kg. Rash, peripheral neuropathy, fatigue, alopecia, and nausea were the most common treatment-related adverse events (TRAEs); the most common TRAEs were grade 1-2 in severity. Among the 112 patients with mUC treated with single-agent EV 1.25 mg/kg, the investigator-assessed confirmed objective response rate (ORR) was 43%, and duration of response was 7.4 months. Median overall survival (OS) was 12.3 months, and the OS rate at 1 year was 51.8%. Similar ORR and estimated median OS were observed in patients >/= 75 years of age with and without prior anti-PD-(L)1 treatment, liver metastases, or upper-tract disease. CONCLUSION: Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC; survival data are encouraging. A pivotal phase II and a confirmatory phase III study are ongoing.

Author Info: (1) Memorial Sloan Kettering Cancer Center, New York, NY. (2) Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. (3) H. Lee Moffitt Cancer Center

Author Info: (1) Memorial Sloan Kettering Cancer Center, New York, NY. (2) Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. (3) H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL. (4) University of Michigan, Ann Arbor, MI. (5) Tom Baker Cancer Centre, Calgary, Alberta, Canada. (6) University of Colorado Comprehensive Cancer Center, Aurora, CO. (7) University of Kansas Cancer Center, Fairway, KS. (8) University of Wisconsin Carbone Cancer Center, Madison, WI. (9) Fox Chase Cancer Center, Philadelphia, PA. (10) Cross Cancer Institute, Edmonton, Alberta, Canada. (11) Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI. (12) University of Miami, Miami, FL. (13) University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA. (14) Stanford University, Stanford, CA. (15) UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC. (16) Astellas Pharma, Northbrook, IL. (17) Seattle Genetics, Bothell, WA. (18) Astellas Pharma, Northbrook, IL. (19) Astellas Pharma, Northbrook, IL. (20) Yale School of Medicine, New Haven, CT.

"UniCAR"-modified off-the-shelf NK-92 cells for targeting of GD2-expressing tumour cells

Antigen-specific redirection of immune effector cells with chimeric antigen receptors (CARs) demonstrated high therapeutic potential for targeting cancers of different origins. Beside CAR-T cells, natural killer (NK) cells represent promising alternative effectors that can be combined with CAR technology. Unlike T cells, primary NK cells and the NK cell line NK-92 can be applied as allogeneic off-the-shelf products with a reduced risk of toxicities. We previously established a modular universal CAR (UniCAR) platform which consists of UniCAR-expressing immune cells that cannot recognize target antigens directly but are redirected by a tumour-specific target module (TM). The TM contains an antigen-binding moiety fused to a peptide epitope which is recognized by the UniCAR molecule, thereby allowing an on/off switch of CAR activity, and facilitating flexible targeting of various tumour antigens depending on the presence and specificity of the TM. Here, we provide proof of concept that it is feasible to generate a universal off-the-shelf cellular therapeutic based on UniCAR NK-92 cells targeted to tumours expressing the disialoganglioside GD2 by GD2-specific TMs that are either based on an antibody-derived single-chain fragment variable (scFv) or an IgG4 backbone. Redirected UniCAR NK-92 cells induced specific killing of GD2-expressing cells in vitro and in vivo, associated with enhanced production of interferon-gamma. Analysis of radiolabelled proteins demonstrated that the IgG4-based format increased the in vivo half-life of the TM markedly in comparison to the scFv-based molecule. In summary, UniCAR NK-92 cells represent a universal off-the-shelf platform that is highly effective and flexible, allowing the use of different TM formats for specific tumour targeting.

Author Info: (1) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. (2) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of R

Author Info: (1) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. (2) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. (3) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. (4) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. (5) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. (6) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. (7) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. National Center for Tumor Diseases (NCT), University Hospital 'Carl Gustav Carus', TU Dresden, Dresden, Germany. (8) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. Semmelweis University, Department of Biophysics and Radiation Biology, Budapest, Hungary. (9) Semmelweis University, Department of Biophysics and Radiation Biology, Budapest, Hungary. (10) Semmelweis University, Department of Biophysics and Radiation Biology, Budapest, Hungary. (11) University of Pannonia, Veszprem, Hungary. (12) Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany. German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, and German Cancer Research Center (DKFZ), Heidelberg, Germany. (13) Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany. German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, and German Cancer Research Center (DKFZ), Heidelberg, Germany. (14) Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt am Main, Germany. (15) Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle, Germany. (16) Department of Pediatric Hematology and Oncology, University Children s Hospital Munster, Munster, Germany. (17) German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. National Center for Tumor Diseases (NCT), University Hospital 'Carl Gustav Carus', TU Dresden, Dresden, Germany. Department of Neurosurgery, Section Experimental Neurosurgery and Tumor Immunology, University Hospital 'Carl Gustav Carus', TU Dresden, Dresden, Germany. (18) Expermintal Transfusion Medicine, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany. (19) German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. Expermintal Transfusion Medicine, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany. Center for Regenerative Therapies Dresden, Dresden, Germany. (20) German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. National Center for Tumor Diseases (NCT), University Hospital 'Carl Gustav Carus', TU Dresden, Dresden, Germany. Center for Regenerative Therapies Dresden, Dresden, Germany. Institute of Immunology, Medical Faculty 'Carl Gustav Carus', TU Dresden, Dresden, Germany. (21) Department of Dermatology and National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. (22) Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Medical Center Heidelberg, Heidelberg, Germany. (23) Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany. German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, and German Cancer Research Center (DKFZ), Heidelberg, Germany. Frankfurt Cancer Institute, Goethe University, Frankfurt am Main, Germany. (24) Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Dresden, Germany. m.bachmann@hzdr.de. German Cancer Consortium (DKTK), partner site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany. m.bachmann@hzdr.de. National Center for Tumor Diseases (NCT), University Hospital 'Carl Gustav Carus', TU Dresden, Dresden, Germany. m.bachmann@hzdr.de. Tumor Immunology, University Cancer Center (UCC) 'Carl Gustav Carus', TU Dresden, Dresden, Germany. m.bachmann@hzdr.de.

CRISPR-engineered T cells in patients with refractory cancer

CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase I clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRalpha (TRAC) and TCRbeta (TRBC) were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding PD-1 (PDCD1), was performed to improve anti-tumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Though chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene-editing for cancer immunotherapy.

Author Info: (1) Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. edward.stadtmauer@pennmedicine.upenn.ed

Author Info: (1) Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. edward.stadtmauer@pennmedicine.upenn.edu cjune@upenn.edu. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4) Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (5) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (6) Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (7) Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (8) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (9) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (10) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (11) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (12) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (13) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (14) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (15) Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (16) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (17) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (18) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (19) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (20) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (21) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (22) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (23) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (24) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (25) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (26) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (27) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (28) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (29) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (30) Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (31) Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (32) Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (33) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (34) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (35) Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. (36) Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (37) Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. (38) Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. (39) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (40) Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (41) Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. edward.stadtmauer@pennmedicine.upenn.edu cjune@upenn.edu. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Tumor Microenvironment-Associated Extracellular Matrix Components Regulate NK Cell Function

The tumor microenvironment (TME) is composed of multiple infiltrating host cells (e.g., endothelial cells, fibroblasts, lymphocytes, and myeloid cells), extracellular matrix, and various secreted or cell membrane-presented molecules. Group 1 innate lymphoid cells (ILCs), which includes natural killer (NK) cells and ILC1, contribute to protecting the host against cancer and infection. Both subsets are able to quickly produce cytokines such as interferon gamma (IFN-gamma), chemokines, and other growth factors in response to activating signals. However, the TME provides many molecules that can prevent the potential effector function of these cells, thereby protecting the tumor. For example, TME-derived tumor growth factor (TGF)-beta and associated members of the superfamily downregulate NK cell cytotoxicity, cytokine secretion, metabolism, proliferation, and induce effector NK cells to upregulate ILC1-like characteristics. In concert, a family of carbohydrate-binding proteins called galectins, which can be produced by different cells composing the TME, can downregulate NK cell function. Matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) are also enzymes that can remodel the extracellular matrix and shred receptors from the tumor cell surface, impairing the activation of NK cells and leading to less effective effector functions. Gaining a better understanding of the characteristics of the TME and its associated factors, such as infiltrating cells and extracellular matrix, could lead to tailoring of new personalized immunotherapy approaches. This review provides an overview of our current knowledge on the impact of the TME and extracellular matrix-associated components on differentiation, impairment, and function of NK cells.

Author Info: (1) Cellular Biology Department, Federal University of Parana, Curitiba, Brazil. (2) Cellular Biology Department, Federal University of Parana, Curitiba, Brazil. (3) Diamantina Ins

Author Info: (1) Cellular Biology Department, Federal University of Parana, Curitiba, Brazil. (2) Cellular Biology Department, Federal University of Parana, Curitiba, Brazil. (3) Diamantina Institute, Translational Research Institute, University of Queensland, Brisbane, QLD, Australia.

Efficacy and toxicity for CD22/CD19 chimeric antigen receptor T-cell therapy in patients with relapsed/refractory aggressive B-cell lymphoma involving the gastrointestinal tract

Gastrointestinal (GI) tract is the most common site of extranodal involvement in non-Hodgkin lymphoma. Life-threatening complications of GI may occur because of tumor or chemotherapy. Chimeric antigen receptor (CAR) T-cell therapy has been successfully used to treat refractory/relapse B-cell lymphoma, however, little is known about the efficacy and safety of CAR-T cell therapy for GI lymphoma. Here, we reported the efficacy and safety of CAR-T cell therapy in 14 patients with relapsed/refractory aggressive B-cell lymphoma involving the GI tract. After a sequential anti-CD22/anti-CD19 CAR-T therapy, 10 patients achieved an objective response, and seven patients achieved a complete response. CAR transgene and B-cell aplasia persisted in the majority of patients irrespective of response status. Six patients with partial response or stable disease developed progressive disease; two patients lost target antigens. Cytokine release syndrome (CRS) and GI adverse events were generally mild and manageable. The most common GI adverse events were diarrhea (4/14), vomiting (3/14) and hemorrhage (2/14). No perforation occurred during follow-up. Infection is a severe complication in GI lymphoma. Two patients were infected with bacteria that are able to colonize at GI; one died of sepsis early after CAR-T cells infusion. In conclusion, our study showed promising efficacy and safety of CAR-T cell therapy in refractory/relapsed B-cell lymphoma involving the GI tract. However, the characteristics of CAR-T-related infection in GI lymphoma should be further clarified to prevent and control infection.

Author Info: (1) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (2) Department of Hematology, Tongji Hospital, T

Author Info: (1) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (2) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (3) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (4) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (5) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (6) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (7) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (8) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (9) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (10) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (11) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (12) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. (13) Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: cello316@163.com.

T follicular helper and T follicular regulatory cells in colorectal cancer: A double-edged sword

Colorectal cancer is considered to be one of the major causes of morbidity and mortality all over the world. The recent discovery of T Follicular helper (TFR) and T follicular regulatory (TFH) which are two opposite subsets of follicular T cells that have been demonstrated to be involved in the process of tumorigenesis. CXCR5(+)CD4(+) follicular T helper cells (TFH) are specialized B cell stimulators. On the other hand, CD4(+)CXCR5(+)Foxp3(+) follicular regulatory T cells (TFR) cell subset can control humoral immune response by suppressing TFH-mediated B-cell activation and antibody production via PD-1 receptor which is highly expressed on its surface. Although, many studies reported the implication of TFH and TFR in human colorectal cancer, their functional role in human colorectal cancer (CRC) is relatively unknown. Under the control of certain cytokines and B-cell lymphoma 6 transcription factor (Bcl-6); the major transcription factor of TFH cells; TFH can expand to the other distinct CD4 (+) T helper cells (TH1, TH2 and TH17) which exert different role in the development of CRC. The aim of this review is to discuss these suggested roles of the two-opposite subset of follicular T cells in the colorectal cancer immune-pathogenesis.

Author Info: (1) Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Department of Medical Microbiology and Immunology, Faculty of Medicine, Assi

Author Info: (1) Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt. (2) Sohag General Hospital, Sohag, Egypt. (3) Department of Microbiology and Immunology, Faculty of Pharmacy, Deraya University, Minia, Egypt. (4) Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Assiut, Egypt. (5) Assiut University Faculty of Medicine, Assiut University, Assiut, Egypt. (6) Department of Tropical Medicine and Gastroenterology, Assiut University Hospital, Assiut, Egypt. (7) Branch of Biotechnology, Department of Biology, College of Science, Mustansiriyah University, POX 10244 Baghdad, Iraq; Faculty of Science and Engineering, School of Engineering, University of Plymouth, Plymouth PL4 8AA, UK. Electronic address: israa.alkadmy@plymouth.ac.uk.

Trastuzumab Emtansine: Mechanisms of Action and Resistance, Clinical Progress, and Beyond

The approval of ado-trastuzumab emtansine (T-DM1) for clinical use represented a turning point both in HER2-positive breast cancer treatment and antibody-drug conjugate (ADC) technology. T-DM1 has proved its value and effectiveness in advanced metastatic disease as well as in the adjuvant setting. However, its therapeutic potential extends beyond the treatment of breast cancer. Around 100 clinical trials have evaluated or are studying different aspects of T-DM1, such as its role in other HER2 malignancies, rational combinations with immunotherapy, or its function in brain metastasis. Conceptually, many lessons can be learned from this ADC. Understanding its mechanisms of action and the molecular basis underlying resistance to T-DM1 may be relevant to comprehend resistances raised to other ADCs and identify pitfalls that may be overcome.

Author Info: (1) Instituto de Biologia Molecular y Celular del Cancer-CSIC, CIBERONC and IBSAL, Salamanca, Spain; Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain. (2) Exper

Author Info: (1) Instituto de Biologia Molecular y Celular del Cancer-CSIC, CIBERONC and IBSAL, Salamanca, Spain; Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain. (2) Experimental Therapeutics Unit, Hospital Clinico San Carlos, Madrid, Spain; CIBERONC and Centro Regional de Investigaciones Biomedicas (CRIB), Castilla La Mancha University, Albacete, Spain. (3) Instituto de Biologia Molecular y Celular del Cancer-CSIC, CIBERONC and IBSAL, Salamanca, Spain. Electronic address: atanasio@usal.es.

Intratumoral delivery of CCL25 enhances immunotherapy against triple-negative breast cancer by recruiting CCR9(+) T cells

CCR9(+) T cells have an increased potential to be activated and therefore may mediate strong antitumor responses. Here, we found, however, that CCL25, the only chemokine for CCR9(+) cells, is not expressed in human or murine triple-negative breast cancers (TNBCs), raising a hypothesis that intratumoral delivery of CCL25 may enhance antitumor immunotherapy in TNBCs. We first determined whether this approach can enhance CD47-targeted immunotherapy using a tumor acidity-responsive nanoparticle delivery system (NP-siCD47/CCL25) to sequentially release CCL25 protein and CD47 small interfering RNA in tumor. NP-siCD47/CCL25 significantly increased infiltration of CCR9(+)CD8(+) T cells and down-regulated CD47 expression in tumor, resulting in inhibition of tumor growth and metastasis through a T cell-dependent immunity. Furthermore, the antitumor effect of NP-siCD47/CCL25 was synergistically enhanced when used in combination with programmed cell death protein-1/programmed death ligand-1 blockades. This study offers a strategy to enhance immunotherapy by promoting CCR9(+)CD8(+) T cell tumor infiltration.

Author Info: (1) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. N

Author Info: (1) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. (2) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. (3) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. (4) Institute of Translational Medicine, China Medical University, Liaoning, China. (5) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. International Center of Future Science, Jilin University, Changchun, Jilin, China. (6) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. International Center of Future Science, Jilin University, Changchun, Jilin, China. National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. (7) Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, Guangdong, China. (8) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. (9) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. (10) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. (11) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. (12) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. (13) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. (14) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. (15) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. (16) Institutes for Life Sciences and School of Medicine, South China University of Technology, Guangzhou, Guangdong, China. (17) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. (18) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. International Center of Future Science, Jilin University, Changchun, Jilin, China. National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. (19) Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Institute of Immunology, The First Hospital, Jilin University, Changchun, Jilin, China. International Center of Future Science, Jilin University, Changchun, Jilin, China. National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Changchun, Jilin, China. State Key Laboratory of Supramolecular Structure and Materials, Jilin University, Changchun, Jilin, China.

Regulation of PD-L1 expression in cancer and clinical implications in immunotherapy

PD-1/PD-L1 immune checkpoint blockade therapy has become an effective method for the treatment of cancers in the clinic. It has great clinical advantages and therapeutic effects in the treatment of various cancers. However, a considerable number of cancer patients currently have relatively low response rates and drug resistance to PD-1/PD-L1 immunotherapy. Therefore, an in-depth understanding of the regulatory mechanism of PD-L1 expression in tumor cells will provide new insights into PD-1/PD-L1 immunotherapy. This review will systematically review the regulatory mechanisms of PD-L1 including genomic amplification, epigenetic regulation, transcriptional regulation, translational regulation and posttranslational modification. We will also discuss PD-L1 expression regulation in clinical applications. Finally, we hope to provide new routes for PD-1/PD-L1 immunotherapy in the clinic.

Author Info: (1) School of Medicine, Jiangsu University Zhenjiang, P. R. China. (2) Department of General Surgery, Nanjing Lishui District People's Hospital, Zhongda Hospital Lishui Branch, Sou

Author Info: (1) School of Medicine, Jiangsu University Zhenjiang, P. R. China. (2) Department of General Surgery, Nanjing Lishui District People's Hospital, Zhongda Hospital Lishui Branch, Southeast University Nanjing, P. R. China. (3) School of Medicine, Jiangsu University Zhenjiang, P. R. China. (4) Institute of Life Sciences, Jiangsu University Zhenjiang, Jiangsu, P. R. China.

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.