Abstract:
:Chimeric antigen receptor (CAR) T-cell therapy is effective in the treatment of cancers of hematopoietic origin. In the immunosuppressive solid tumor environment, CAR T cells encounter obstacles that compromise their efficacy. We developed a strategy to address these barriers by having CAR T cells secrete single-domain antibody fragments [variable heavy domain of heavy chain antibodies (VHH) or nanobodies] that can modify the intratumoral immune landscape and thus support CAR T-cell function in immunocompetent animals. VHHs are small in size and able to avoid domain swapping when multiple nanobodies are expressed simultaneously-features that can endow CAR T cells with desirable properties. The secretion of an anti-CD47 VHH by CAR T cells improves engagement of the innate immune system, enables epitope spreading, and can enhance the antitumor response. CAR T cells that secrete anti-PD-L1 or anti-CTLA-4 nanobodies show improved persistence and demonstrate the versatility of this approach. Furthermore, local delivery of secreted anti-CD47 VHH-Fc fusions by CAR T cells at the tumor site limits their systemic toxicity. CAR T cells can be further engineered to simultaneously secrete multiple modalities, allowing for even greater tailoring of the antitumor immune response.
journal_name
Cancer Immunol Resjournal_title
Cancer immunology researchauthors
Xie YJ,Dougan M,Ingram JR,Pishesha N,Fang T,Momin N,Ploegh HLdoi
10.1158/2326-6066.CIR-19-0734subject
Has Abstractpub_date
2020-04-01 00:00:00pages
518-529issue
4eissn
2326-6066issn
2326-6074pii
2326-6066.CIR-19-0734journal_volume
8pub_type
杂志文章abstract::Macrophage-mediated cytotoxicity is controlled by surface receptor expression and activation. Despite the numerous studies documenting the role of macrophage C-type lectin receptors (CLR) in pathogen elimination, little is known about their contribution to antitumor responses. Here, we report that IL13 inhibits T-cell...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-18-0213
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journal_title:Cancer immunology research
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doi:10.1158/2326-6066.CIR-17-0489
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-16-0400
更新日期:2017-08-01 00:00:00
abstract::CD47-specific antibodies and fusion proteins that block CD47-SIRPα signaling are employed as antitumor agents for several cancers. Here, we investigated the synergistic antitumor effect of simultaneously targeting CD47 and autophagy in non-small cell lung cancer (NSCLC). SIRPαD1-Fc, a novel CD47-targeting fusion prote...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-16-0398
更新日期:2017-05-01 00:00:00
abstract::Chronic inflammation drives colitis-associated colorectal cancer (CAC) in inflammatory bowel disease (IBD). FoxP3+ regulatory T cells (Treg) coexpressing the Th17-related transcription factor RORγt accumulate in the lamina propria of IBD patients, where they are thought to represent an intermediate stage of developmen...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-17-0698
更新日期:2018-09-01 00:00:00
abstract::Cancer immunology has recently made major therapeutic inroads that represent clinical application of basic insights into mechanisms that govern immunity against tumors. Research into fundamental elements of T-cell and natural killer-cell biology, including the basis of antigen recognition, activation, proliferation, a...
journal_title:Cancer immunology research
pub_type: 杂志文章,评审
doi:10.1158/2326-6066.CIR-14-0153
更新日期:2014-10-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-20-0312
更新日期:2020-11-11 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-17-0159
更新日期:2018-01-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-15-0141
更新日期:2015-12-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-19-0690
更新日期:2020-04-01 00:00:00
abstract::Caspase recuitment domain-containing protein 9 (CARD9) functions in different inflammation pathways to elicit responses to microbial signals and is known to affect intestinal inflammation. Examining the APC(min) mouse model of intestinal tumorigenesis and using stringently controlled, sex- and age-matched pairs of CAR...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-14-0148
更新日期:2015-07-01 00:00:00
abstract::Many immunotherapeutic approaches under development rely on T-cell recognition of cancer-derived peptides bound to human leukocyte antigen molecules on the cell surface. Direct experimental demonstration that such peptides are processed and bound is currently challenging. Here, we describe a method that meets this cha...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-19-0107
更新日期:2019-11-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-14-0180
更新日期:2015-12-01 00:00:00
abstract::Infectious agents play an etiologic role in approximately 20% of cancer cases worldwide. Eleven pathogens (seven viruses, three parasites, and one bacterium) are known to contribute to oncogenesis either directly via the expression of their protein products or indirectly via chronic inflammation. Although prevention o...
journal_title:Cancer immunology research
pub_type: 杂志文章,评审
doi:10.1158/2326-6066.CIR-13-0179
更新日期:2014-01-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章,评审
doi:10.1158/2326-6066.CIR-15-0194
更新日期:2015-11-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-15-0200-T
更新日期:2016-03-01 00:00:00
abstract::Individuals of African descent are disproportionately affected by specific complex diseases, such as breast and prostate cancer, which are driven by both biological and nonbiological factors. In the case of breast cancer, there is clear evidence that psychosocial factors (environment, socioeconomic status, health beha...
journal_title:Cancer immunology research
pub_type: 杂志文章,评审
doi:10.1158/2326-6066.CIR-18-0564
更新日期:2019-09-01 00:00:00
abstract::Granulocytic-macrophage colony-stimulating factor (GM-CSF) is used as an adjuvant in cancer vaccine trials and has the potential to enhance antitumor efficacy with immunotherapy; however, its immunologic effects are not fully understood. Here, we report results from a phase I study of neoadjuvant GM-CSF in patients wi...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-16-0042
更新日期:2016-11-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-19-0556
更新日期:2020-06-01 00:00:00
abstract::The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, I...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-13-0136
更新日期:2014-04-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-13-0042
更新日期:2013-12-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-18-0256
更新日期:2019-01-01 00:00:00
abstract::In hepatocellular carcinoma (HCC), surgical resection is associated with high recurrence rate, and no effective adjuvant therapy currently exists. We initiated a pilot randomized trial of perioperative immunotherapy with nivolumab and ipilimumab for resectable HCC. Here, we provide an illustrative report of a case tha...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-18-0605
更新日期:2019-09-01 00:00:00
abstract::Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, wit...
journal_title:Cancer immunology research
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doi:10.1158/2326-6066.CIR-15-0297
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journal_title:Cancer immunology research
pub_type: 杂志文章,评审
doi:10.1158/2326-6066.CIR-15-0143
更新日期:2015-08-01 00:00:00
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journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-18-0633
更新日期:2019-03-01 00:00:00
abstract::One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor-infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T c...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-17-0502
更新日期:2018-07-01 00:00:00
abstract::Programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors have shown activity in metastatic clear cell renal cell carcinoma (ccRCC). Data on the activity of these agents in patients with non-clear cell RCC (nccRCC) or patients with sarcomatoid/rhabdoid differentiation are limited. In this multicenter analysis, we e...
journal_title:Cancer immunology research
pub_type: 杂志文章,多中心研究
doi:10.1158/2326-6066.CIR-17-0475
更新日期:2018-07-01 00:00:00
abstract::Several host factors may affect the spread of cancer to distant organs; however, the intrinsic role of dendritic cells (DC) in controlling metastasis is poorly described. Here, we show in several tumor models that although the growth of primary tumors in Batf3-deficient mice, which lack cross-presenting DCs, was not d...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-17-0341
更新日期:2017-12-01 00:00:00
abstract::Despite HER2-targeted therapies improving the outcome of HER2+ breast cancer, many patients experience resistance and metastatic progression. Cancer stem cells (CSC) play a role in this resistance and progression, thus combining HER2 targeting with CSC inhibition could improve the management of HER2+ breast cancer. Th...
journal_title:Cancer immunology research
pub_type: 杂志文章
doi:10.1158/2326-6066.CIR-20-0082
更新日期:2020-08-01 00:00:00