Combining Immune Checkpoint Inhibitors With Conventional Cancer Therapy

Yan, Yiyi; Kumar, Anagha; Finnes, Heidi D.; Park, Sean S.; Dronca, Roxana S.; Dong, Haidong

doi:10.3389/fimmu.2018.01739

Cited by 185 publications

(155 citation statements)

References 119 publications

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“…In conclusion, this study discloses some of the functional pathways of TIM-3 + TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients.Vaccines 2020, 8, 71 2 of 17 checkpoints (IC) in suppression of anti-tumor immune responses to various malignancies provided new targets for immunotherapy. Despite the clinical efficacy of current available immunotherapies in cancer patients, a large proportion of CRC patients fail to respond mainly due to immune-cell mediated resistance [2].T-cell immunoglobulin and mucin domain containing 3 (TIM-3) is a member of mucin domain transmembrane protein family, which was initially recognized on CD4 + T helper 1 (Th1) and CD8 + T cytotoxic (Tc1) cells [3,4]. Later studies revealed that TIM-3 can also be expressed on other immune subsets, including T regulatory cells (Tregs) [5].…”

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confidence: 99%

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Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

et al. 2020

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T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4− (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3− counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients.

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confidence: 99%

“…Vaccines 2020, 8, 71 2 of 17 checkpoints (IC) in suppression of anti-tumor immune responses to various malignancies provided new targets for immunotherapy. Despite the clinical efficacy of current available immunotherapies in cancer patients, a large proportion of CRC patients fail to respond mainly due to immune-cell mediated resistance [2].…”

mentioning

confidence: 99%

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

et al. 2020

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“…Previous investigators studied other combinations of conventional cytotoxic drugs and immunotherapies to achieve enhanced effects and overcome tumor resistance to classical chemotherapy (Yan et al, 2018). Since cytotoxic drugs may be either immunostimulatory or immunosuppressive (Nowak et al, 2006), it is important to find synergistic combinations and recognize antagonistic combinations.…”

Section: Discussionmentioning

confidence: 99%

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

et al. 2019

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The long‐term survival of osteosarcoma patients with metastatic or recurrent disease remains dismal, and new therapeutic options are urgently needed. The purpose of our study was to compare the efficacy of CD47 mAb plus doxorubicin combination therapy in mouse models of osteosarcoma with CD47 mAb and doxorubicin monotherapy. Forty‐eight NOD scid gamma (NSG) mice with intratibial MNNG/HOS tumors received CD47 mAb, doxorubicin, combination therapy, or control IgG treatment. Twenty‐four mice (n = 6 per group) underwent pre‐ and post‐treatment magnetic resonance imaging (MRI) scans with the macrophage marker ferumoxytol, bioluminescence imaging, and histological analysis. Tumor ferumoxytol enhancement, tumor flux, and tumor‐associated macrophages (TAM) density were compared between different groups using a one‐way ANOVA. Twenty‐four additional NSG mice underwent survival analyses with Kaplan–Meier curves and a log‐rank (Mantel–Cox) test. Intratibial osteosarcomas demonstrated significantly stronger ferumoxytol enhancement and significantly increased TAM quantities after CD47 mAb plus doxorubicin combination therapy compared to CD47 mAb (P = 0.02) and doxorubicin monotherapy (P = 0.001). Tumor‐bearing mice treated with CD47 mAb plus doxorubicin combination therapy demonstrated significantly reduced tumor size and prolonged survival compared to control groups that received CD47 mAb (P = 0.03), doxorubicin monotherapy (P = 0.01), and control IgG (P = 0.001). In conclusion, CD47 mAb plus doxorubicin therapy demonstrates an additive therapeutic effect in mouse models of osteosarcomas, which can be monitored with an immediately clinically applicable MRI technique.

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“…[ 7,9–11 ] As such, the potential for immunotherapy to synergize with traditional treatments has been proposed and clinically verified in multiple therapeutic settings. [ 12,13 ]…”

Section: Introductionmentioning

confidence: 99%

Poly(cyclodextrin)‐Polydrug Nanocomplexes as Synthetic Oncolytic Virus for Locoregional Melanoma Chemoimmunotherapy

Kim

Sestito

et al. 2020

Adv Funct Materials

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Despite the approval of oncolytic virus (OV) therapy for advanced melanoma, its intrinsic limitations that include the risk of persistent viral infection and cost-intensive manufacturing motivate the development of analogous approaches that are free from the disadvantages of virus-based therapies. Herein, reported is a nanoassembly comprised of multivalent host-guest interactions between polymerized paclitaxel (pPTX) and nitric oxide-incorporated polymerized β-cyclodextrin (pCD-pSNO) that through its bioactive components and when used locoregionally recapitulates the therapeutic effects of OV. The resultant pPTX/pCD-pSNO exhibits significantly enhanced cytotoxicity, immunogenic cell death, dendritic cell (DC) activation, and T cell expansion in vitro compared to free agents alone or in combination. In vivo, intratumoral administration of pPTX/pCD-pSNO results in activation and expansion of DCs systemically, but with a corresponding expansion of myeloid-derived suppressor cells and suppression of CD8 + T cell expansion.When combined with antibody targeting cytotoxic T lymphocyte antigen-4 that blunts this molecule's signaling effects on T cells, intratumoral pPTX/pCD-pSNO treatment elicits potent anticancer effects that significantly prolong animal survival. This formulation thus leverages the chemo-and immunotherapeutic synergies of PTX and nitric oxide and suggests the potential for virusfree nanoformulations to mimic the therapeutic action and benefits of OVs.

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Combining Immune Checkpoint Inhibitors With Conventional Cancer Therapy

Cited by 185 publications

References 119 publications

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

Poly(cyclodextrin)‐Polydrug Nanocomplexes as Synthetic Oncolytic Virus for Locoregional Melanoma Chemoimmunotherapy

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