Cancer immunology, immunotherapy : CII最新文献

{"title":"Antitumor efficacy of BAFF-R targeting CAR T cells manufactured under clinic-ready conditions.","authors":"Zhenyuan Dong,&nbsp;Wesley A Cheng,&nbsp;D Lynne Smith,&nbsp;Brian Huang,&nbsp;Tiantian Zhang,&nbsp;Wen-Chung Chang,&nbsp;Xiuli Wang,&nbsp;Stephen J Forman,&nbsp;Larry W Kwak,&nbsp;Hong Qin","doi":"10.1007/s00262-020-02614-8","DOIUrl":"https://doi.org/10.1007/s00262-020-02614-8","url":null,"abstract":"<p><p>B-cell malignancies can potentially be cured by CD19 chimeric antigen receptor (CAR) T-cell therapy. Although clinical response rates can be up to 93% in acute lymphoblastic leukemia, treatment-related antigen loss and lack of therapeutic persistence contribute to disease relapse. These shortcomings of current CAR T-cell therapy indicate the need for biologically relevant target selection and for improving the efficacy and persistence of the CAR T cells, which we have addressed by developing a novel B-cell activating factor receptor (BAFF-R) CAR T-cell therapy with improved therapeutic persistence. BAFF-R is a B-cell survival receptor and highly expressed in B-cell malignancies. We developed a prototype CAR T cell that efficiently and specifically eliminated BAFF-R expressing human B-cell tumors in several xenogeneic mouse models, including models of CD19 antigen loss. We proceeded with translational development and validation of BAFF-R CAR T cells produced under current good manufacturing practices (cGMP). cGMP-grade BAFF-R CAR T cells underwent in vitro and in vivo validation in established models to confirm that the potency and efficacy of our original research modeling was replicated. Food and Drug Administration required release testing was performed to ensure our BAFF-R CAR T cells meet specifications for new drug products. Completing and exceeding these requirements, the data fully support the initiation of a first-in-human Phase 1 trial for BAFF-R-positive relapsed/refractory (r/r) B-ALL.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"2139-2145"},"PeriodicalIF":5.8,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00262-020-02614-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37975070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of immune checkpoints and T cell exhaustion markers in early and advanced stages of colorectal cancer.","authors":"Reem Saleh,&nbsp;Rowaida Z Taha,&nbsp;Salman M Toor,&nbsp;Varun Sasidharan Nair,&nbsp;Khaled Murshed,&nbsp;Mahwish Khawar,&nbsp;Mahmood Al-Dhaheri,&nbsp;Mahir Abdulla Petkar,&nbsp;Mohamed Abu Nada,&nbsp;Eyad Elkord","doi":"10.1007/s00262-020-02593-w","DOIUrl":"https://doi.org/10.1007/s00262-020-02593-w","url":null,"abstract":"<p><p>Despite recent advances in colorectal cancer (CRC) treatment, a large proportion of patients show limited responses to therapies, especially in advanced stages. There is an urgent need to identify prognostic biomarkers and/or therapeutic targets in advanced stages, aiming to improve the efficacy of current treatments. We aimed to determine prognostic biomarkers in tumor tissue and circulation of CRC patients, with a special focus on T cell exhaustion markers. We found that mRNA levels of PD-1, TIM-3, CTLA-4, TIGIT, CD160, CD244, KLRG1, TOX2, TOX3, Ki-67, and PRDM1 were elevated in CRC tumor tissues. We also investigated differences in gene expression between early and advanced disease stages. We found that TOX and potentially TIM-3, CTLA-4, VISTA, TIGIT, KLRG1, TOX2, SIRT1, Ki-67, and Helios mRNA levels in tumor tissue were elevated in advanced disease stages, suggesting their potential roles in CRC progression. In contrast, PD-1 and CD160 levels in tumor tissue were downregulated in advanced stages. In the circulation of CRC patients, mRNA levels of PD-1, VISTA and LAG-3 were higher than those of healthy individuals. Moreover, in circulation, PD-1, CTLA-4 and TIGIT mRNA levels were reduced in advanced stages. Interestingly, levels of PD-1 in both tumor tissue and circulation were reduced in advanced stages, suggesting that targeting PD-1 in patients with advanced stages could be less effective. Altogether, these findings suggest some potential T cell exhaustion markers that could be utilized as prognostic biomarkers and/or therapeutic targets for CRC. However, further investigations and validations in larger cohorts are required to confirm these findings.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"1989-1999"},"PeriodicalIF":5.8,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00262-020-02593-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37922299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NKG2D-Fc fusion protein promotes antitumor immunity through the depletion of immunosuppressive cells.","authors":"Po-Hao Feng,&nbsp;Brandon Lam,&nbsp;Ssu-Hsueh Tseng,&nbsp;Yu-Jui Kung,&nbsp;Emily Farmer,&nbsp;Max A Cheng,&nbsp;Chien-Fu Hung","doi":"10.1007/s00262-020-02615-7","DOIUrl":"https://doi.org/10.1007/s00262-020-02615-7","url":null,"abstract":"<p><p>A major factor impeding the success of numerous therapeutic approaches in cancer is the immunosuppressive nature of the tumor microenvironment (TME). Hence, methods capable of reverting tumor immunosuppression through depletion or reprogramming of myeloid-derived suppressive cells (MDSCs) and regulatory T cells (Tregs) are of great clinical need. Here, we explore NKG2D-Fc as a modality to modulate antitumor immunity through the depletion of immunosuppressive MDSCs and Tregs in the TME. We have generated the NKG2D-Fc fusion protein and characterized its potential to mediate tumor control and overall survival in LL2 and MC38 murine models. Upon treatment of LL2 or MC38 tumor-bearing mice with NKG2D-Fc, we observe significant tumor control and enhanced survival compared to Fc control. When characterizing MDCSs and Tregs from tumor-bearing mice, we observe clear expression of NKG2D-ligand RAE1γ and subsequent binding of NKG2D-Fc fusion protein to both MDSCs and Tregs. Examining the immune profile of mice treated with NKG2D-Fc reveals significant depletion of MDSCs and Tregs in the TME, as well as an increase in NK cells likely due to the reversed suppressive TME. In conclusion, NKG2D-Fc induces antitumor immunity and tumor control through the depletion of MDSCs and Tregs, subsequently providing a niche for the infiltration and expansion of proinflammatory cells, such as NK cells. Strategies capable of modulating the immunosuppressive state in cancer are in high clinical demand. NKG2D-Fc is a simple, single tool capable of depleting both MDSCs and Tregs and should be further investigated as a therapeutic agent for the treatment of cancer.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"2147-2155"},"PeriodicalIF":5.8,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00262-020-02615-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37984883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrity of plasma DNA is inversely correlated with vaccine-induced antitumor immunity in ovarian cancer patients.","authors":"Kayoko Waki,&nbsp;Kanako Yokomizo,&nbsp;Kouichiro Kawano,&nbsp;Naotake Tsuda,&nbsp;Nobukazu Komatsu,&nbsp;Akira Yamada","doi":"10.1007/s00262-020-02599-4","DOIUrl":"https://doi.org/10.1007/s00262-020-02599-4","url":null,"abstract":"<p><p>Cancer immunotherapy including vaccine therapy is a promising modality for cancer treatment, but few patients show its clinical benefits currently. The identification of biomarkers that can identify patients who will benefit from cancer immunotherapy is thus important. Here, we investigated the potential utility of the circulating cell-free DNA (cfDNA) integrity-a ratio of necrotic cell-derived, longer DNA fragments versus apoptotic cell-derived shorter fragments of Alu gene-as a biomarker of vaccine therapy for patients with ovarian cancer. We analyzed plasma samples from 39 patients with advanced or recurrent ovarian cancer enrolled in clinical trials for personalized peptide vaccinations. We observed that (1) the cfDNA integrity was decreased after the first cycle of vaccination, and (2) the decreased levels of cfDNA integrity were correlated with vaccine-induced immune responses; i.e., decreased cfDNA integrity was observed in 91.7% and 59.3% of the IgG-positive and negative patients, respectively (p = 0.0445). Similarly, decreased cfDNA integrity was observed in 92.9% and 56.0% of CTL response-positive and negative patients, respectively (p = 0.0283). These results suggest that the circulating cfDNA integrity is a possible biomarker for cancer vaccine therapy.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"2001-2007"},"PeriodicalIF":5.8,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00262-020-02599-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37922300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of CDX-527: a bispecific antibody combining PD-1 blockade and CD27 costimulation for cancer immunotherapy.","authors":"Laura A Vitale,&nbsp;Li-Zhen He,&nbsp;Lawrence J Thomas,&nbsp;Anna Wasiuk,&nbsp;Thomas O'Neill,&nbsp;Jenifer Widger,&nbsp;Andrea Crocker,&nbsp;Laura Mills-Chen,&nbsp;Eric Forsberg,&nbsp;Jeffrey Weidlick,&nbsp;Colleen Patterson,&nbsp;Russell A Hammond,&nbsp;James Boyer,&nbsp;Crystal Sisson,&nbsp;Diego Alvarado,&nbsp;Joel Goldstein,&nbsp;Henry C Marsh,&nbsp;Tibor Keler","doi":"10.1007/s00262-020-02610-y","DOIUrl":"https://doi.org/10.1007/s00262-020-02610-y","url":null,"abstract":"<p><p>CD27 is a costimulatory molecule that provides a complementary target to the PD-1/PD-L1 checkpoint axis on T cells. Combining a CD27 agonist antibody with PD-1/PD-L1 blockade has shown synergistic antitumor activity in preclinical models, which led to clinical studies of the combination in cancer patients. We theorized that coupling CD27 costimulation with PD-1/PD-L1 blockade in a bispecific antibody (BsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced CD27 activation by cross-linking through PD-L1 and Fc receptors. To test this approach, we developed CDX-527, a tetravalent PD-L1xCD27 IgG1-scFv BsAb. CDX-527 potently inhibits PD-1 signaling and induces CD27-mediated T cell costimulation through PD-L1 cross-linking. In mixed lymphocyte reaction assays, CDX-527 is more potent than the combination of the parental antibodies, suggesting that cross-linking through both Fc receptors and PD-L1 results in enhanced CD27 agonist activity. CDX-527 was shown to mediate effector function against tumor cells overexpressing either CD27 or PD-L1. In human CD27 transgenic mice, we observed that antigen-specific T cell responses to a vaccine are greatly enhanced with a surrogate PD-L1xCD27 BsAb. Furthermore, the BsAb exhibits greater antitumor activity than the combination of the parental antibodies in a syngeneic lymphoma model. A pilot study of CDX-527 in cynomolgus macaques confirmed a mAb-like pharmacokinetic profile without noted toxicities. These studies demonstrate that CDX-527 effectively combines PD-1 blockade and CD27 costimulation into one molecule that is more potent than combination of the parental antibodies providing the rationale to advance this BsAb toward clinical studies in cancer patients.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"2125-2137"},"PeriodicalIF":5.8,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00262-020-02610-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37975069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral blood markers predictive of outcome and immune-related adverse events in advanced non-small cell lung cancer treated with PD-1 inhibitors.","authors":"Lihong Peng,&nbsp;Yong Wang,&nbsp;Fen Liu,&nbsp;Xiaotong Qiu,&nbsp;Xinwei Zhang,&nbsp;Chen Fang,&nbsp;Xiaoyin Qian,&nbsp;Yong Li","doi":"10.1007/s00262-020-02585-w","DOIUrl":"https://doi.org/10.1007/s00262-020-02585-w","url":null,"abstract":"<p><strong>Background: </strong>Selected patients with advanced non-small cell lung cancer (NSCLC) benefit from immunotherapy, especially immune checkpoint inhibitors such as PD-1 (programmed cell death protein 1) inhibitor. Peripheral blood biomarkers would be most convenient to predict treatment outcome and immune-related adverse events (irAEs) in candidate patients. This study explored associations between inflammation-related peripheral blood markers and onset of irAEs and outcome in patients with advanced NSCLC receiving PD-1 inhibitors.</p><p><strong>Methods: </strong>A retrospective analysis was conducted of 102 patients with advanced NSCLC receiving PD-1 inhibitors from January 2017 to May 2019. Cox regression models were employed to assess the prognostic effect of low/high neutrophil/lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and prognostic nutrition index (PNI) on overall survival (OS) and progression-free survival (PFS). Logistic regression models were used to analyze the correlation between peripheral blood markers and the onset of irAEs.</p><p><strong>Result: </strong>NLR < 5, LDH < 240 U/L, or PNI ≥ 45 was favorably associated with significantly better outcomes compared with higher, higher, or lower values, respectively. The multivariate analysis determined that these parameters were independently associated with both better PFS (p = 0.049, 0.046, 0.014, respectively) and longer OS (p = 0.007, 0.031, < 0.001, respectively). Patients with three favorable factors among NLR, LDH, and PNI had better PFS and OS than did those with two, one, or none. PNI and NLR were associated with the onset of irAEs.</p><p><strong>Conclusion: </strong>In patients with advanced NSCLC treated with PD-1 inhibitors, pretreatment NLR, LDH, and PNI may be useful predictive markers of clinical outcome and irAEs.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"1813-1822"},"PeriodicalIF":5.8,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00262-020-02585-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37886331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective targeting of different populations of myeloid-derived suppressor cells by histone deacetylase inhibitors.","authors":"Ayumi Hashimoto,&nbsp;Takeshi Fukumoto,&nbsp;Rugang Zhang,&nbsp;Dmitry Gabrilovich","doi":"10.1007/s00262-020-02588-7","DOIUrl":"https://doi.org/10.1007/s00262-020-02588-7","url":null,"abstract":"<p><p>Myeloid-derived suppressor cells (MDSCs) are widely implicated in negative regulation of immune responses in cancer. Inhibition of class I histone deacetylases (HDAC) with entinostat has anti-MDSC activity. However, as single agent, it did not delay tumor growth in EL4 and LLC tumor models. Here, we found that entinostat reduced immune suppressive activity of only one type of MDSC-polymorphonuclear, PMN-MDSC, whereas it had no effect on monocytic M-MDSC or macrophages. M-MDSC had high amount of class II HDAC-HDAC6, which was further increased after the treatment of mice with entinostat. Inhibition of HDAC6 with ricolinostat reduced suppressive activity of M-MDSC, but did not affect PMN-MDSC or delayed tumor growth. However, combination of entinostat and ricolinostat abrogated suppressive activity of both populations of MDSC and substantially delayed tumor progression. Thus, inactivation of MDSC required targeting of both major subsets of these cells via inhibitors of class I and class II HDAC.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"1929-1936"},"PeriodicalIF":5.8,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00262-020-02588-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37958666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep abscopal response to radiotherapy and anti-PD-1 in an oligometastatic melanoma patient with unfavorable pretreatment immune signature.","authors":"Tsubasa Watanabe,&nbsp;Elke Firat,&nbsp;Jutta Scholber,&nbsp;Simone Gaedicke,&nbsp;Corinne Heinrich,&nbsp;Ren Luo,&nbsp;Nicolas Ehrat,&nbsp;Gabriele Multhoff,&nbsp;Annette Schmitt-Graeff,&nbsp;Anca-Ligia Grosu,&nbsp;Amir Abdollahi,&nbsp;Jessica C Hassel,&nbsp;Dagmar von Bubnoff,&nbsp;Frank Meiss,&nbsp;Gabriele Niedermann","doi":"10.1007/s00262-020-02587-8","DOIUrl":"https://doi.org/10.1007/s00262-020-02587-8","url":null,"abstract":"<p><p>Radiotherapy can elicit abscopal effects in non-irradiated metastases, particularly under immune checkpoint blockade (ICB). We report on two elderly patients with oligometastatic melanoma treated with anti-PD-1 and stereotactic body radiation therapy (SBRT). Before treatment, patient 1 showed strong tumor infiltration with exhausted CD8+ T cells and high expression of T cell-attracting chemokines. This patient rapidly mounted a complete response, now ongoing for more than 4.5 years. Patient 2 exhibited low CD8+ T cell infiltration and high expression of immunosuppressive arginase. After the first SBRT, his non-irradiated metastases did not regress and new metastases occurred although neoepitope-specific and differentiation antigen-specific CD8+ T cells were detected in the blood. A second SBRT after 10 months on anti-PD-1 induced a radiologic complete response correlating with an increase in activated PD-1-expressing CD8 T cells. Apart from a new lung lesion, which was also irradiated, this deep abscopal response lasted for more than 2.5 years. However, thereafter, his disease progressed and the activated PD-1-expressing CD8 T cells dropped. Our data suggest that oligometastatic patients, where a large proportion of the tumor mass can be irradiated, are good candidates to improve ICB responses by RT, even in the case of an unfavorable pretreatment immune signature, after progression on anti-PD-1, and despite advanced age. Besides repeated irradiation, T cell epitope-based immunotherapies (e.g., vaccination) may prolong antitumor responses even in patients with unfavorable pretreatment immune signature.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"1823-1832"},"PeriodicalIF":5.8,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00262-020-02587-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37886330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune biological rationales for the design of combined radio- and immunotherapies.","authors":"Michael Hader,&nbsp;Benjamin Frey,&nbsp;Rainer Fietkau,&nbsp;Markus Hecht,&nbsp;Udo S Gaipl","doi":"10.1007/s00262-019-02460-3","DOIUrl":"https://doi.org/10.1007/s00262-019-02460-3","url":null,"abstract":"<p><p>Cancer immunotherapies are promising treatments for many forms of cancer. Nevertheless, the response rates to, e.g., immune checkpoint inhibitors (ICI), are still in low double-digit percentage. This calls for further therapy optimization that should take into account combination of immunotherapies with classical tumor therapies such as radiotherapy. By designing multimodal approaches, immune modulatory properties of certain radiation schemes, additional immune modulation by immunotherapy with ICI and hyperthermia, as well as patient stratification based on genetic and immune constitutions have to be considered. In this context, both the tumor and its microenvironment including cells of the innate and adaptive immune system have to be viewed in synopsis. Knowledge of immune activation and immune suppression by radiation is the basis for well-elaborated addition of certain immunotherapies. In this review, the focus is set on additional immune stimulation by hyperthermia and restoration of an immune response by ICI. The impact of radiation dose and fractionation on immune modulation in multimodal settings has to be considered, as the dynamics of the immune response and the timing between radiotherapy and immunotherapy. Another big challenge is the patient stratification that should be based on matrices of biomarkers, taking into account genetics, proteomics, radiomics, and \"immunomics\". One key aim is to turn immunological \"cold\" tumors into \"hot\" tumors, and to eliminate barriers of immune-suppressed or immune-excluded tumors. Comprehensive knowledge of immune alterations induced by radiation and immunotherapy when being applied together should be utilized for patient-adapted treatment planning and testing of innovative tumor therapies within clinical trials.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"293-306"},"PeriodicalIF":5.8,"publicationDate":"2020-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00262-019-02460-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37557343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical assessment of transiently TCR redirected T cells for solid tumour immunotherapy.","authors":"Nadia Mensali,&nbsp;Marit Renée Myhre,&nbsp;Pierre Dillard,&nbsp;Sylvie Pollmann,&nbsp;Gustav Gaudernack,&nbsp;Gunnar Kvalheim,&nbsp;Sébastien Wälchli,&nbsp;Else Marit Inderberg","doi":"10.1007/s00262-019-02356-2","DOIUrl":"https://doi.org/10.1007/s00262-019-02356-2","url":null,"abstract":"<p><p>Off-target toxicity due to the expression of target antigens in normal tissue or TCR cross-reactivity represents a major risk when using T cell receptor (TCR)-engineered T cells for treatment of solid tumours. Due to the inherent cross-reactivity of TCRs it is difficult to accurately predict their target recognition pre-clinically. It has become evident that direct testing in a human being represents the best evaluation of the risks. There is, therefore, a clear unmet need for assessing the safety of a therapeutic TCR in a more controllable manner than by the injection of permanently modified cellular products. Using transiently modified T cells combined with dose escalation has already been shown feasible for chimeric antigen receptor (CAR)-engineered T cells, but nothing is yet reported for TCR. We performed a preclinical evaluation of a therapeutic TCR transiently expressed in T cells by mRNA electroporation. We analyzed if the construct was active in vitro, how long it was detectable for and if this expression format was adapted to in vivo efficacy assessment. Our data demonstrate the potential of mRNA engineered T cells, although less powerful than permanent redirection, to induce a significant response. Thus, these findings support the development of mRNA based TCR-therapy strategies as a feasible and efficacious method for evaluating TCR safety and efficacy in first-in-man testing.</p>","PeriodicalId":520581,"journal":{"name":"Cancer immunology, immunotherapy : CII","volume":" ","pages":"1235-1243"},"PeriodicalIF":5.8,"publicationDate":"2019-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s00262-019-02356-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37068673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}