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BackgroundGene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells.MethodsFour cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay.ResultsResponses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients.ConclusionsOur studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy.Trial registrationClinicalTrials.gov, NCT01343043 , Registered 27 April 2011.

Phagocytosis and oxidative burst are two major effector arms of innate immunity. Although it is known that both are activated by Toll-like receptors (TLRs) and Rac GTPases, how their strengths are controlled in quiescent and TLR-activated cells is not clear. We report here that TIPE2 (TNFAIP8L2) serves as a negative regulator of innate immunity by linking TLRs to Rac. TLRs control the expression levels of TIPE2, which in turn dictates the strengths of phagocytosis and oxidative burst by binding to and blocking Rac GTPases. Consequently, TIPE2 knockout cells have enhanced phagocytic and bactericidal activities and TIPE2 knockout mice are resistant to bacterial infection. Thus, TIPE2 sets the strengths of phagocytosis and oxidative burst and may be targeted to effectively control infections. [ABSTRACT FROM AUTHOR]

Background: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10 + tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-003 was a phase I dose-escalation trial that aimed to evaluate the safety and antitumor activity of ADP-A2M10 in non-small cell lung cancer (NSCLC) (NCT02592577)., Methods: Eligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08-0.12×10 9 (dose group 1), 0.5-1.2×10 9 (dose group 2), and 1.2-15×10 9 (dose group 3/expansion) transduced cells., Results: Eleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three patients received cells in dose group 1, dose group 2, and dose group 3/expansion, respectively. The most frequently reported grade ≥3 adverse events were lymphopenia (n=11), leukopenia (n=10), neutropenia (n=8), anemia (n=6), thrombocytopenia (n=5), and hyponatremia (n=5). Three patients presented with cytokine release syndrome (grades 1, 2, and 4, respectively). One patient received the highest dose of lymphodepletion (fludarabine 30 mg/m 2 on days -5 to -2 and cyclophosphamide 1800 mg/m 2 on days -5 to -4) prior to a second infusion of ADP-A2M10 and had a partial response, subsequently complicated by aplastic anemia and death. Responses included: partial response (after second infusion; one patient), stable disease (four patients), clinical or radiographic progressive disease (five patients), and not evaluable (one patient). ADP-A2M10 were detectable in peripheral blood and in tumor tissue. Peak persistence was higher in patients who received higher doses of ADP-A2M10., Conclusions: ADP-A2M10 demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity. There was persistence of ADP-A2M10 in peripheral blood as well as ADP-A2M10 trafficking into the tumor. Given the discovery that MAGE-A10 and MAGE-A4 expression frequently overlap, this clinical program closed as trials with SPEAR T cells targeting MAGE-A4 are ongoing., Competing Interests: Competing interests: AG holds stock options in Adaptimmune. AJO has received research contracts from Alkermes, Antegene, Astellas, Checkmate, Gan & Lee, GlycoNex, InstilBio, Intensity, Istari, Kadmon, Kartos, NeoImmune, NGM, OncoSec, Sound Bio, SpringBank, Takeda; has received payment for advisory board roles from Merck, BMS, Pfizer, Takeda, Sanofi, Eisai. DB, DM, EN, JB, J-MN, JPS, MMP, NH, RB, SF are or were employees of Adaptimmune at the time of the study. GRB has received grants/contracts from Amgen, Bayer, Adaptimmune, Elelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, Torque, AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Xcovery, Tmunity Therapeutics, Regeneron, Beigene, Repertoire Immune Medicines, Verastem; consulting fees from Abbvie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Gilead, Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Tyme Oncology, Xcovery, Virogin Biotech, Maverick Therapeutics; has participated on a Data Safety Monitoring Board or Advisory Board for Virogen Biotech, Maverick Therapeutics; holds stock or stock options in Virogin Biotech; and has other financial or non-financial interests in Johnson & Johnson/Janssen (immediate family member employed). JG has been a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo, Pfizer, Incyte, Novartis, Merck, Agios, Amgen, Jounce, Karyopharm, GlydeBio, Mirati, AstraZeneca, Regeneron, Oncorus, Helsinn, Array, and Clovis Oncology; has been an employee (immediate family member) with equity in Ironwood Pharmaceuticals; has received research funding from Novartis, Genentech/Roche, and Ariad/Takeda; has received institutional research support from Tesaro, Moderna, Blueprint, Scholar Rock, BMS, Array, Adaptimmune, Novartis, Genentech/Roche, Alexo and Merck. JVH has received grants/contracts from AstraZeneca, GlaxoSmithKline and Spectrum; holds royalty/licenses in Spectrum; has received consulting fees from AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, RefleXion; has received honoraria from Medlinker, Peerview, Nexus Health Medicine, Targeted Oncology, MJH Events; has received support for attending meetings from IASLC Targeted Therapies, IASLC World Conference on Lung Cancer; has been in a leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Mechanisms of Cancer Therapeutics-1 (MCT1) (Study Section – Chair). MJ has received research funding from AbbVie, Acerta, Adaptimmune, Apexigen, Array BioPharma, AstraZeneca, Atreca, BeiGene, Boehringer Ingelheim, Checkpoint Therapeutics, Corvus Pharmaceuticals, CytomX, Daiichi Sankyo, Dynavax, Lilly, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics, Neovia Oncology, Novartis, OncoMed Pharmaceuticals, Pfizer, Regeneron Pharmaceuticals, Sanofi, Seven and Eight Biopharmaceuticals, Shattuck Labs, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, University of Michigan, WindMIL, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, Amgen; has held a consulting/advisory role (spouse) for Astellas, Otsuka Pharmaceuticals; has held a consulting/advisory role (self) for AbbVie, Achilles Therapeutics, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Genentech, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Lilly, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi, Association of Community Cancer Center; has received food/beverage/travel expenses from Abbvie, Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, EMD Serono, Bristol Myers Squibb, Exelixis, Genentech/Roche, Incyte, Merck, Pfizer, Sysmex Inostics, Vapotherm, Janssen, Lilly, Novartis, Sanofi. MJE has received research funding from GlaxoSmithKline, Mersana, Amgen, Windmil, Nektar, Apexigen, Adaptimmune; has received consulting fees from Kanaph, Flame; has received honoraria from Sanofi; has been a member of DSMB for AstraZeneca, Seattle Genetics, GlaxoSmithKline, Takeda; has been a consultant/on an advisory board for Windmil, Regeneron, Syndax; has been the Chair, Scientific Advisory board for Lung Cancer Foundation of America; has been the Deputy Editor of 'Lung Cancer'; has received stock options from Biomarker strategies; Creatv Biotech. MJF has been a consultant for Arcellx, BMS, Novartis, Kite, Iovance. PMF is an employee of Adaptimmune; holds stock in Adaptimmune and Bristol-Myers Squib; has received compensation for travel and congress meetings. RG has received consulting fees from BMS, Abbvie, Geneplus; has participated on a Data Safety Monitoring Board or Advisory Board for Roche Genentech. SD has been a consultant for Jacobio pharmaceuticals (without financial compensation). TH was an employee of Adaptimmune at the time of the study; has been a consultant for Adaptimmune. VKL has been in a consulting or advisory role for Takeda, Bristol-Myers Squibb, Seattle Genetics; has received research funding from GlaxoSmithKline, Bristol-Myers Squibb, Guardant Health, Takeda. VM has received consulting fees from Roche, Bayer, Pieris, BMS, Janssen and Basilea. BDdS, CB, ZW have nothing to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The TIPE (tumor necrosis factor-α-induced protein 8-like) family are newly described regulators of immunity and tumorigenesis consisting of four highly homologous mammalian proteins: TNFAIP8 (tumor necrosis factor-α-induced protein 8), TIPE1 (TNFAIP8-like 1, or TNFAIP8L1), TIPE2 (TNFAIP8L2) and TIPE3 (TNFAIP8L3). They are the only known transfer proteins of the lipid secondary messengers PIP2 (phosphatidylinositol 4,5-bisphosphate) and PIP3 (phosphatidylinositol 3,4,5-trisphosphate). Cell-surface receptors, such as G-protein-coupled receptors and receptor tyrosine kinases, regulate inflammation and cancer via several signaling pathways, including the nuclear factor (NF)-κB and phosphoinositide-3 kinase (PI3K) pathways, the latter of which is upstream of both Akt and STAT3 activation. An expression analysis in humans demonstrated that the TIPE family is dysregulated in cancer and inflammation, and studies both in mice and in vitro have demonstrated that this family of proteins plays a critical role in tumorigenesis and inflammatory responses. In this review, we summarize the current literature for all four family members, with a special focus on the phenotypic manifestations present in the various knockout murine strains, as well as the related cell signaling that has been elucidated to date.