Journal Articles

CD3 bispecific antibody-induced cytokine release is dispensable for cytotoxic T cell activity

Spotlight 

To study cytokine release, Li and Piskol et al. used an immune competent HER2-positive spontaneous mammary tumor mouse model and a human PBMC in vitro model. In vitro and in vivo, primary, but not repeat, exposure to CD3/HER2 bispecific antibody induced T cells to express IL-2, IFNγ, and TNFα. However, repeat antibody exposure induced perforin and granzyme expression and mediated T cell cytolysis. TNFα provoked monocyte expression of IL-6 and IL-1β, which correlated with systemic cytokine release. Prophylactic blocking of TNFα mitigated systemic cytokines while preserving T cell antitumor effects.

Contributed by Paula Hochman

To study cytokine release, Li and Piskol et al. used an immune competent HER2-positive spontaneous mammary tumor mouse model and a human PBMC in vitro model. In vitro and in vivo, primary, but not repeat, exposure to CD3/HER2 bispecific antibody induced T cells to express IL-2, IFNγ, and TNFα. However, repeat antibody exposure induced perforin and granzyme expression and mediated T cell cytolysis. TNFα provoked monocyte expression of IL-6 and IL-1β, which correlated with systemic cytokine release. Prophylactic blocking of TNFα mitigated systemic cytokines while preserving T cell antitumor effects.

Contributed by Paula Hochman

T cell-retargeting therapies have transformed the therapeutic landscape of oncology. Regardless of the modality, T cell activating therapies are commonly accompanied by systemic cytokine release, which can progress to deadly cytokine release syndrome (CRS). Because of incomplete mechanistic understanding of the relationship between T cell activation and systemic cytokine release, optimal toxicity management that retains full therapeutic potential remains unclear. Here, we report the cell type-specific cellular mechanisms that link CD3 bispecific antibody-mediated killing to toxic cytokine release. The immunologic cascade is initiated by T cell triggering, whereas monocytes and macrophages are the primary source of systemic toxic cytokine release. We demonstrate that T cell-generated tumor necrosis factor-alpha (TNF-alpha) is the primary mechanism mediating monocyte activation and systemic cytokine release after CD3 bispecific treatment. Prevention of TNF-alpha release is sufficient to impair systemic release of monocyte cytokines without affecting antitumor efficacy. Systemic cytokine release is only observed upon initial exposure to CD3 bispecific antibody not subsequent doses, indicating a biological distinction between doses. Despite impaired cytokine release after second exposure, T cell cytotoxicity remained unaffected, demonstrating that cytolytic activity of T cells can be achieved in the absence of cytokine release. The mechanistic uncoupling of toxic cytokines and T cell cytolytic activity in the context of CD3 bispecifics provides a biological rationale to clinically explore preventative treatment approaches to mitigate toxicity.

Author Info: (1) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (2) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (3) Genentech Inc., 1 DNA Way, South San Franc

Author Info: (1) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (2) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (3) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (4) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (5) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (6) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (7) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (8) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (9) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (10) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. (11) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. junttila.teemu@gene.com junttila.melissa@gene.com. (12) Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. junttila.teemu@gene.com junttila.melissa@gene.com.

Intratumoral immunotherapy with TLR7/8 agonist MEDI9197 modulates the tumor microenvironment leading to enhanced activity when combined with other immunotherapies

BACKGROUND: Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically "cold" tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated. METHODS: The response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models. RESULTS: Targeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNalpha, IL-12 and IFNgamma. In contrast, a STING or a TLR9 agonist primarily induces release of IFNalpha. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8(+) T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models. CONCLUSION: Localized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.

Author Info: (1) R&D Oncology, AstraZeneca Ltd, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK. stefanie.mullins@astrazeneca.com. (2) 3M Drug Delivery Systems Division, 3M Center Bld

Author Info: (1) R&D Oncology, AstraZeneca Ltd, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK. stefanie.mullins@astrazeneca.com. (2) 3M Drug Delivery Systems Division, 3M Center Bldg 260-3A-14, St. Paul, MN, 55144, USA. (3) R&D Oncology, AstraZeneca Ltd, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK. (4) 3M Drug Delivery Systems Division, 3M Center Bldg 260-3A-14, St. Paul, MN, 55144, USA. (5) 3M Drug Delivery Systems Division, 3M Center Bldg 260-3A-14, St. Paul, MN, 55144, USA. (6) 3M Drug Delivery Systems Division, 3M Center Bldg 260-3A-14, St. Paul, MN, 55144, USA. (7) R&D Oncology, AstraZeneca Ltd, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK. (8) R&D Biopharmaceuticals, Pathology, Drug Safety and Metabolism, AstraZeneca Ltd, Cambridge, UK. (9) R&D Oncology, AstraZeneca Ltd, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK. (10) R&D Oncology, AstraZeneca Ltd, 1 MedImmune Way, Gaithersburg, MD, 20878, USA. (11) R&D Oncology, AstraZeneca Ltd, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK. (12) R&D Oncology, AstraZeneca Ltd, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK. (13) R&D Oncology, AstraZeneca Ltd, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK. (14) 3M Drug Delivery Systems Division, 3M Center Bldg 260-3A-14, St. Paul, MN, 55144, USA. (15) 3M Drug Delivery Systems Division, 3M Center Bldg 260-3A-14, St. Paul, MN, 55144, USA. (16) R&D Biopharmaceuticals, Pathology, Drug Safety and Metabolism, AstraZeneca Ltd, Cambridge, UK. (17) R&D Oncology, AstraZeneca Ltd, 1 MedImmune Way, Gaithersburg, MD, 20878, USA. (18) 3M Drug Delivery Systems Division, 3M Center Bldg 260-3A-14, St. Paul, MN, 55144, USA. (19) R&D Oncology, AstraZeneca Ltd, Aaron Klug Building, Granta Park, Cambridge, CB21 6GH, UK. wilkinsonr@medimmune.com.

Late-differentiated effector neoantigen-specific CD8+ T cells are enriched in peripheral blood of non-small cell lung carcinoma patients responding to atezolizumab treatment

BACKGROUND: There is strong evidence that immunotherapy-mediated tumor rejection can be driven by tumor-specific CD8+ T cells reinvigorated to recognize neoantigens derived from tumor somatic mutations. Thus, the frequencies or characteristics of tumor-reactive, mutation-specific CD8+ T cells could be used as biomarkers of an anti-tumor response. However, such neoantigen-specific T cells are difficult to reliably identify due to their low frequency in peripheral blood and wide range of potential epitope specificities. METHODS: Peripheral blood mononuclear cells (PBMC) from 14 non-small cell lung cancer (NSCLC) patients were collected pre- and post-treatment with the anti-PD-L1 antibody atezolizumab. Using whole exome sequencing and RNA sequencing we identified tumor neoantigens that are predicted to bind to major histocompatibility complex class I (MHC-I) and utilized mass cytometry, together with cellular 'barcoding', to profile immune cells from patients with objective response to therapy (n = 8) and those with progressive disease (n = 6). In parallel, a highly-multiplexed combinatorial tetramer staining was used to screen antigen-specific CD8+ T cells in peripheral blood for 782 candidate tumor neoantigens and 71 known viral-derived control peptide epitopes across all patient samples. RESULTS: No significant treatment- or response associated phenotypic difference were measured in bulk CD8+ T cells. Multiplexed peptide-MHC multimer staining detected 20 different neoantigen-specific T cell populations, as well as T cells specific for viral control antigens. Not only were neoantigen-specific T cells more frequently detected in responding patients, their phenotypes were also almost entirely distinct. Neoantigen-specific T cells from responder patients typically showed a differentiated effector phenotype, most like Cytomegalovirus (CMV) and some types of Epstein-Barr virus (EBV)-specific CD8+ T cells. In contrast, more memory-like phenotypic profiles were observed for neoantigen-specific CD8+ T cells from patients with progressive disease. CONCLUSION: This study demonstrates that neoantigen-specific T cells can be detected in peripheral blood in non-small cell lung cancer (NSCLC) patients during anti-PD-L1 therapy. Patients with an objective response had an enrichment of neoantigen-reactive T cells and these cells showed a phenotype that differed from patients without a response. These findings suggest the ex vivo identification, characterization, and longitudinal follow-up of rare tumor-specific differentiated effector neoantigen-specific T cells may be useful in predicting response to checkpoint blockade. TRIAL REGISTRATION: POPLAR trial NCT01903993 .

Author Info: (1) immunoSCAPE Pte Ltd, Singapore, Singapore. (2) Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. (3) Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. (4) Gen

Author Info: (1) immunoSCAPE Pte Ltd, Singapore, Singapore. (2) Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. (3) Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. (4) Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. (5) Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. (6) immunoSCAPE Pte Ltd, Singapore, Singapore. (7) immunoSCAPE Pte Ltd, Singapore, Singapore. (8) immunoSCAPE Pte Ltd, Singapore, Singapore. (9) Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore, Singapore. (10) Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. (11) immunoSCAPE Pte Ltd, Singapore, Singapore. (12) immunoSCAPE Pte Ltd, Singapore, Singapore. (13) Genentech, 1 DNA way, South San Francisco, CA, 94080, USA. yadav.mahesh@gene.com.

Novel Human Anti-PD-L1 mAbs Inhibit Immune-Independent Tumor Cell Growth and PD-L1 Associated Intracellular Signalling

The novel antibody-based immunotherapy in oncology exploits the activation of immune system mediated by immunomodulatory antibodies specific for immune checkpoints. Among them, the programmed death ligand-1 (PD-L1) is of particular interest as it is expressed not only on T-cells, but also on other immune cells and on a large variety of cancer cells, such as breast cancer cells, considering its high expression in both ErbB2-positive and Triple Negative Breast Cancers. We demonstrate here that PD-L1_1, a novel anti-PD-L1 T -cell stimulating antibody, inhibits PD-L1-tumor cell growth also by affecting the intracellular MAPK pathway and by activating caspase 3. Similar in vitro results were obtained for the first time here also with the clinically validated anti-PD-L1 mAb Atezolizumab and in vivo with another validated anti-mouse anti-PD-L1 mAb. Moreover, we found that two high affinity variants of PD-L1_1 inhibited tumor cell viability more efficiently than the parental PD-L1_1 by affecting the same MAPK pathways with a more potent effect. Altogether, these results shed light on the role of PD-L1 in cancer cells and suggest that PD-L1_1 and its high affinity variants could become powerful antitumor weapons to be used alone or in combination with other drugs such as the anti-ErbB2 cAb already successfully tested in in vitro combinatorial treatments.

Author Info: (1) Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via Pansini 5, 80131, Napoli, Italy. Ceinge - Biotecnologie Avanzate s.c. a.r.l.

Author Info: (1) Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via Pansini 5, 80131, Napoli, Italy. Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145, Naples, Italy. (2) Nouscom srl, Via di Castel Romano 100, 00128, Rome, Italy. (3) Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via Pansini 5, 80131, Napoli, Italy. Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145, Naples, Italy. (4) Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via Pansini 5, 80131, Napoli, Italy. Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145, Naples, Italy. (5) Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145, Naples, Italy. European School of Molecular Medicine, University of Milan, Via Festa del Perdono 7, 20122, Milan, Italy. (6) Nouscom srl, Via di Castel Romano 100, 00128, Rome, Italy. (7) Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via Pansini 5, 80131, Napoli, Italy. Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145, Naples, Italy. Keires AG Baumleingasse 18, CH-4051, Basel, Switzerland. (8) Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Via Pansini 5, 80131, Napoli, Italy. cladelor@unina.it. Ceinge - Biotecnologie Avanzate s.c. a.r.l., via Gaetano Salvatore 486, 80145, Naples, Italy. cladelor@unina.it.

Mutated RAS: Targeting the "Untargetable" with T-cells

The RAS family of proteins are at the apex of several pathways implicated in a multitude of epithelial cancers, but have remained stubbornly resistant to the wave of targeted small molecules and antibodies that have revolutionized clinical oncology. KRAS, the most commonly mutated of the isoforms, represents an attractive target for treatment given its ubiquity, central role as a driver mutation and association with poor prognosis. This review is a comprehensive summary of the existing approaches to targeting KRAS spanning small molecule inhibitors, cancer vaccines, and with a focus on trials in adoptive cell therapy. Here we explain how the limitations of existing drugs and non-specific immune-based therapies are circumvented with techniques in modern immunotherapy. The successes outlined represent the most promising path to finally targeting the prototypical "undruggable" RAS oncogene family.

Author Info: (1) Surgery Branch, National Cancer Institute praveen.chatani@nih.gov. (2) Surgery Branch, National Cancer Institute.

Author Info: (1) Surgery Branch, National Cancer Institute praveen.chatani@nih.gov. (2) Surgery Branch, National Cancer Institute.

The Role of Natural Killer Cells as a Platform for Immunotherapy in Pediatric Cancers

PURPOSE OF REVIEW: We aim to review the most recent findings in the use of NK cells in childhood cancers. RECENT FINDINGS: Natural killer cells are cytotoxic to tumor cells. In pediatric leukemias, adoptive transfer of NK cells can bridge children not in remission to transplant. Interleukins (IL2, IL15) can enhance NK cell function. NK cell-CAR therapy has advantages of shorter life span that lessens chronic toxicities, lower risk of graft versus host disease when using allogeneic cells, ability of NK cells to recognize tumor cells that have downregulated MHC to escape T cells, and possibly less likelihood of cytokine storm. Cytotoxicity to solid tumors (rhabdomyosarcoma, Ewing's sarcoma, neuroblastoma) is seen with graft versus tumor effect in transplant and in combination with antibodies. Challenges lie in the microenvironment which is suppressive for NK cells. NK cell immunotherapy in childhood cancers is promising and recent works aim to overcome challenges.

Author Info: (1) Division of Paediatric Oncology, Department of Paediatrics, National University Hospital Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 12, Singapore, 119228, Singapore.

Author Info: (1) Division of Paediatric Oncology, Department of Paediatrics, National University Hospital Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 12, Singapore, 119228, Singapore. miriam_kimpo@nuhs.edu.sg. (2) Division of Paediatric Oncology, Department of Paediatrics, National University Hospital Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 12, Singapore, 119228, Singapore. (3) Division of Paediatric Oncology, Department of Paediatrics, National University Hospital Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 12, Singapore, 119228, Singapore.

TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma

Immunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE), and RNA sequencing data from anti-PD1-treated patients at Sheba medical center. TNFSF4 mRNA is expressed in melanoma cell lines and melanoma samples, including those with low lymphocytic infiltrates, and is not associated with the ulceration status of the primary tumor. Low expression of TNFSF4 mRNA is associated with worse prognosis in all melanoma patients and in the cohorts of stage III and stage IIIc-IV patients. Low expression of TNFSF4 mRNAs is also associated with worse prognosis in the subgroup of patients with low lymphocytic infiltrates, suggesting that tumoral TNFSF4 is associated with outcome. TNFSF4 expression was not correlated with the expression of other known checkpoint mRNAs. Last, metastatic patients with TNFSF4 mRNA expression within the lowest quartile have significantly worse outcome on anti-PD1 treatment, and a significantly lower response rate to these agents. Our current work points to TNFSF4 expression in melanoma as a potential determinant of prognosis, and warrants further translational and clinical research.

Author Info: (1) Departments of Melanoma Medical Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. (2) Ella Lemelbau

Author Info: (1) Departments of Melanoma Medical Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. (2) Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. (3) Lab of Molecular Cancer Research, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. (4) Lab of Molecular Cancer Research, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. (5) Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. Lab of Molecular Cancer Research, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. (6) Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. (7) Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. (8) Departments of Melanoma Medical Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. (9) Department of Oncology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. Division of Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. Oncology Institute and Cancer Research Center, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. (10) Lab of Molecular Cancer Research, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. (11) Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. Department of Oncology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. (12) Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. (13) Lab of Molecular Cancer Research, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. (14) Ella Lemelbaum Institute for Immuno-Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. gal.markel@sheba.health.gov.il. Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. gal.markel@sheba.health.gov.il. (15) Department of Oncology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel. Raya.leibowitz-amit@sheba.health.gov.il. Division of Oncology, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. Raya.leibowitz-amit@sheba.health.gov.il. Oncology Institute and Cancer Research Center, Sheba Medical Center-Tel Hashomer, 2 Sheba Road, 5266202, Ramat Gan, Israel. Raya.leibowitz-amit@sheba.health.gov.il.

Adenosine Blockage in Tumor Microenvironment and Improvement of Cancer Immunotherapy

Immunotherapy has been introduced into cancer treatment methods, but different problems have restricted the efficacy of these protocols in clinical trials such as the presence of various immunomodulatory factors in the tumor microenvironment. Adenosine is an immunosuppressive metabolite produced by the tumor to promote growth, invasion, metastasis, and immune evasion. Many studies about adenosine and its metabolism in cancer have heightened interest in pursuing this treatment approach. It seems that targeting the adenosine pathway in combination with immunotherapy may lead to efficient antitumor response. In this review, we provide information on the roles of both adenosine and CD73 in the immune system and tumor development. We also describe recent studies about combination therapy with both purinergic inhibitors and other immunotherapeutic methods.

Author Info: (1) Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran. Department of Tissue Engineering and Applied Cell Sciences, School of Medicine,

Author Info: (1) Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran. Department of Tissue Engineering and Applied Cell Sciences, School of Medicine, Semnan University of Medical Science, Semnan, Iran. (2) Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56

The inhibitory receptors PD-1, Tim-3, and Lag-3 are highly expressed on tumor-infiltrating lymphocytes and compromise their antitumor activity. For efficient cancer immunotherapy, it is important to prevent chimeric antigen receptor T (CAR-T)-cell exhaustion. Here we downregulate these three checkpoint receptors simultaneously on CAR-T cells and that show the resulting PTL-CAR-T cells undergo epigenetic modifications and better control tumor growth. Furthermore, we unexpectedly find increased tumor infiltration by PTL-CAR-T cells and their clustering between the living and necrotic tumor tissue. Mechanistically, PTL-CAR-T cells upregulate CD56 (NCAM), which is essential for their effector function. The homophilic interaction between intercellular CD56 molecules correlates with enhanced infiltration of CAR-T cells, increased secretion of interferon-gamma, and the prolonged survival of CAR-T cells. Ectopically expressed CD56 promotes CAR-T cell survival and antitumor response. Our findings demonstrate that genetic blockade of three checkpoint inhibitory receptors and the resulting high expression of CD56 on CAR-T cells enhances the inhibition of tumor growth.

Author Info: (1) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry o

Author Info: (1) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. Qianyang Biomedical Research Institute, Guangzhou, Guangdong, 510663, China. (2) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (3) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (4) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (5) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (6) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. Qianyang Biomedical Research Institute, Guangzhou, Guangdong, 510663, China. (7) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (8) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (9) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (10) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. (11) Qianyang Biomedical Research Institute, Guangzhou, Guangdong, 510663, China. (12) Qianyang Biomedical Research Institute, Guangzhou, Guangdong, 510663, China. (13) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. liubf5@mail.sysu.edu.cn. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. liubf5@mail.sysu.edu.cn. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. liubf5@mail.sysu.edu.cn. (14) Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China. zhangh92@mail.sysu.edu.cn. Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. zhangh92@mail.sysu.edu.cn. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Guangzhou, Guangdong, 510080, China. zhangh92@mail.sysu.edu.cn. Qianyang Biomedical Research Institute, Guangzhou, Guangdong, 510663, China. zhangh92@mail.sysu.edu.cn.

Immunological Targets for Immunotherapy: Inhibitory T Cell Receptors

Tumor development is characterized by the accumulation of mutational and epigenetic changes that transform normal cells and survival pathways into self-sustaining cells capable of untrammeled growth. Although multiple modalities including surgery, radiation, and chemotherapy are available for the treatment of cancer, the benefits conferred are often limited. The immune system is capable of specific, durable, and adaptable responses. However, cancers hijack immune mechanisms such as negative regulatory checkpoints that have evolved to limit inflammatory and immune responses to thwart effective antitumor immunity. The development of monoclonal antibodies against inhibitory receptors expressed by immune cells has produced durable responses in a broad array of advanced malignancies and heralded a new dawn in the cancer armamentarium. However, these remarkable responses are limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Preclinical and clinical studies with immune checkpoint blockade are exploring the therapeutic potential antibody-based therapy targeting multiple inhibitory receptors. In this chapter, we discuss the current understanding of the structure, ligand specificities, function, and signaling activities of various inhibitory receptors. Additionally, we discuss the current development status of various immune checkpoint inhibitors targeting these negative immune receptors and highlight conceptual gaps in knowledge.

Author Info: (1) Cancer Immunology and Immunotherapeutics Program (CIIP), Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. davard@upmc.edu. (2) Cancer Immunology and Immuno

Author Info: (1) Cancer Immunology and Immunotherapeutics Program (CIIP), Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. davard@upmc.edu. (2) Cancer Immunology and Immunotherapeutics Program (CIIP), Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.

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