Hollow MnO2 as a tumor-microenvironment-responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses

Background: Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov to include phase I/II clinical trials. Data from 39 studies (1906 patients) were included. Of all the agents, Isatuximab (Isa, anti-CD38) and F50067 (anti-CXCR4) were the only mAbs to produce encouraging results as monotherapy with overall response rates (ORRs) of 66.7% and 32% respectively. Isa showed activity when used in combination with lenalidomide (Len) and dexamethasone (Dex), producing a clinical benefit rate (CBR) of 83%. Additionally, Isa used in combination with pomalidomide (Pom) and Dex resulted in a CBR of 73%. Indatuximab Ravtansine (anti-CD138 antibody-drug conjugate) produced an ORR of 78% and 79% when used in combination with Len-Dex and Pom-Dex, respectively. Conclusions: Combination therapy using mAbs such as indatuximab, pembrolizumab, lorvotuzumab, siltuximab or dacetuzumab with chemotherapy agents produced better outcomes as compared to monotherapies. Further clinical trials investigating mAbs targeting CD38 used in combination therapy are warranted.

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The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment

Viruses ◽

10.3390/v13071200 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1200

Author(s):

Ifeanyi Kingsley Uche ◽

Konstantin G. Kousoulas ◽

Paul J. F. Rider

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Tumor Microenvironment ◽

Immune Responses ◽

Virus Type ◽

Herpes Simplex Virus Type ◽

Checkpoint Inhibitors ◽

Significant Proportion ◽

Simplex Virus

The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.

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Tumor Microenvironment-Triggered In-Situ Cancer Vaccines with Dual Immunogenic Cell Death Inductions for Elevated Antitumor and Antimetastatic Therapy

Nanoscale ◽

10.1039/d1nr02018h ◽

2021 ◽

Author(s):

Jun Lin ◽

Binbin Ding ◽

Pan Zheng ◽

Dong Li ◽

Meifang Wang ◽

...

Keyword(s):

Cell Death ◽

Tumor Microenvironment ◽

Immune Responses ◽

Cancer Immunotherapy ◽

Cancer Vaccines ◽

High Specificity ◽

The Body ◽

Immunogenic Cell Death ◽

Specific Antigens

Cancer vaccine is to make tumor-specific antigens into vaccines, which then are injected back into the body to activate immune responses for cancer immunotherapy. Despite the high specificity and therapeutic...

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Cyto-KIK: A phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps4598 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS4598-TPS4598

Author(s):

Karie Runcie ◽

Eric A. Singer ◽

Moshe Chaim Ornstein ◽

Christopher B. Anderson ◽

Matthew Dallos ◽

...

Keyword(s):

Clinical Trial ◽

Tumor Microenvironment ◽

Immune Responses ◽

Phase Ii ◽

Checkpoint Inhibitors ◽

Recurrent Glioblastoma ◽

Phase Iii ◽

Cytoreductive Nephrectomy ◽

Open Label ◽

Orthotopic Mouse Model

TPS4598 Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy removes a large portion of the tumor which may be a source of immunosuppression driven by tumor cell-intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition generated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- naïve subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluorescence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: NCT04322955.

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Phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib) (Cyto-KIK).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.tps371 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. TPS371-TPS371

Author(s):

Karie Runcie ◽

Eric A. Singer ◽

Moshe Chaim Ornstein ◽

Christopher B. Anderson ◽

Matthew Dallos ◽

...

Keyword(s):

Clinical Trial ◽

Tumor Microenvironment ◽

Immune Responses ◽

Phase Ii ◽

Checkpoint Inhibitors ◽

Recurrent Glioblastoma ◽

Phase Iii ◽

Cytoreductive Nephrectomy ◽

Open Label ◽

Orthotopic Mouse Model

TPS371 Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy removes a large portion of the tumor which may be a source of immunosuppression driven by tumor cell-intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition generated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- naïve subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluorescence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: AAAS6927 .

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A Near-Infrared Light-Excitable Immunomodulating Nano-photosensitizer for Effective Photoimmunotherapy

Biomaterials Science ◽

10.1039/d1bm00569c ◽

2021 ◽

Author(s):

Yadan Zheng ◽

Zhanzhan Zhang ◽

Qi Liu ◽

Ying Wang ◽

Jialei Hao ◽

...

Keyword(s):

Photodynamic Therapy ◽

Tumor Microenvironment ◽

Immune Responses ◽

Near Infrared ◽

Tumor Ablation ◽

Infrared Light ◽

Near Infrared Light ◽

Therapeutic Efficiency ◽

Immunosuppressive Tumor Microenvironment

Photodynamic therapy has great potential for tumor ablation and the activation of antitumor immune responses. However, its overall therapeutic efficiency is often limited by the immunosuppressive tumor microenvironment. We developed...

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B234 Dasatinib and Dexamethasone Combination Therapy Targets Myeloma and the Tumor Microenvironment

Clinical Lymphoma & Myeloma ◽

10.1016/s1557-9190(11)70692-8 ◽

2009 ◽

Vol 9 ◽

pp. S116-S117

Author(s):

KA Ramasamy ◽

L Macpherson ◽

G Mufti ◽

S Schey ◽

Y Calle

Keyword(s):

Tumor Microenvironment ◽

Combination Therapy ◽

Therapy Targets

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Combination therapy using molecular-targeted drugs modulates tumor microenvironment and impairs tumor growth in renal cell carcinoma

Cancer Medicine ◽

10.1002/cam4.1124 ◽

2017 ◽

Vol 6 (10) ◽

pp. 2308-2320 ◽

Cited By ~ 5

Author(s):

Hiroyuki Kitano ◽

Yasuhiko Kitadai ◽

Jun Teishima ◽

Ryo Yuge ◽

Shunsuke Shinmei ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tumor Microenvironment ◽

Combination Therapy ◽

Tumor Growth ◽

Cell Carcinoma ◽

Renal Cell ◽

Targeted Drugs

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Targeting regulatory T cells for immunotherapy in melanoma

Molecular Biomedicine ◽

10.1186/s43556-021-00038-z ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Lili Huang ◽

Yeye Guo ◽

Shujing Liu ◽

Huaishan Wang ◽

Jinjin Zhu ◽

...

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Regulatory T Cells ◽

Immune Responses ◽

Immune Cells ◽

Therapeutic Efficacy ◽

Patient Survival ◽

Therapeutic Antibodies ◽

Promising Strategy ◽

Fine Tune

AbstractRegulatory T cells (Tregs) are essential in the maintenance of immunity, and they are also a key to immune suppressive microenvironment in solid tumors. Many studies have revealed the biology of Tregs in various human pathologies. Here we review recent understandings of the immunophenotypes and suppressive functions of Tregs in melanoma, including Treg recruitment and expansion in a tumor. Tregs are frequently accumulated in melanoma and the ratio of CD8+ T cells versus Tregs in the melanoma is predictive for patient survival. Hence, depletion of Tregs is a promising strategy for the enhancement of anti-melanoma immunity. Many recent studies are aimed to target Tregs in melanoma. Distinguishing Tregs from other immune cells and understanding the function of different subsets of Tregs may contribute to better therapeutic efficacy. Depletion of functional Tregs from the tumor microenvironment has been tested to induce clinically relevant immune responses against melanomas. However, the lack of Treg specific therapeutic antibodies or Treg specific depleting strategies is a big hurdle that is yet to be overcome. Additional studies to fine-tune currently available therapies and more agents that specifically and selectively target tumor infiltrating Tregs in melanoma are urgently needed.

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Gamma-interferon inducible lysosomal thiolreductase (GILT) effect on breast tumor microenvironment through regulating CXCR6/CXCL16 axis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15081 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15081-e15081

Author(s):

YinJiao Fei ◽

MingXing Liang ◽

Lei Li ◽

Yuxin Song ◽

Zhen Liu ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Immune Responses ◽

Western Blot ◽

Cell Line ◽

Gamma Interferon ◽

Gene Set Enrichment Analysis ◽

High Expression ◽

Axillary Lymph ◽

Potential Biomarker

e15081 Background: Gamma-interferon Inducible Lysosomal Thiolreductase (GILT) is constitutively expressed in most antigens endocytosed by antigen presenting cells (APCs), and its function is to catalyze the reduction of disulfide (S-S) bonds in protein substrates. The cytokine CXCL16 is one of the only two known plasma membrane chemokines which induces chemotaxis of activated T cells and bone marrow plasma cells in tumor microenvironment. It contains a free end folded by two sulfur bonds and therefore could also be a zymolyte of GILT. Previous studies found that specific receptor of CXCL16, CXCR6, was significantly overexpressed in breast cancer tissues and metastatic axillary lymph nodes. We suppose whether CXCR6/CXCL16 axis is regulated by GILT and affect tumor microenvironment, thereby eliciting specific anti-tumor immune responses in breast cancer (BC). Methods: GILT expression in BC was evaluated using publicly available data from The Cancer Genome Atlas (TCGA). GILT gene was analyzed in UALCAN ( http://ualcan.path.uab.edu/analysis-prot.html ) . In vitro, Immunohistochemistry (IHC) was conducted to examine the location and relation of GILT and CXCR6. Gene Set Enrichment Analysis (GSEA) was performed to mine the biological pathways involved in BC related GILT regulatory network. The expression of GILT at protein and RNA levels were detected by Western Blot and RT-PCR assay. Overexpression and knockdown of GILT in BC cell lines was carried out to further analyzed the correlation between GILT and CXCL16/CXCR6. Results: TCGA database showed that GILT expression was increased in the stroma of BC compared with normal, and was correlated to shorter BC overall survival. GSEA suggested that the expression of GILT was associated with chemotactic factors. Pearson analysis and IHC showed GILT had a strong correlation with CXCL16/CXCR6 axis in the aspect of angiogenesis and immunity. qRT-PCR and Western Blot assay also revealed that GILT had high expression in BC. Besides, patients with high expression of GILT in IHC simultaneously showed high immunoreactive to macrophage markers, which was related to neovascularization and anti-tumor immune responses. Compared with the normal breast cell line MCF-10A, GILT protein had high expression in Hs578T and low expression in MDA-MB-231 cell line. GILT was overexpressed in MDA-MB-231 and knockdown in Hs578T. Result showed that high level GILT promoted the production of CXCL16/CXCR6,while GILT siRNA knockdown inhibited the production of CXCL16/CXCR6. Conclusions: GILT could catalyze CXCL16 in BC, function as a key mechanism to affect tumor microenvironment through CXCR6/CXCL16 pathway. GILT-activated CXCL16 levels showed a strong connection with unfavorable outcomes in BC, which could be a potential biomarker of prognosis and a novel therapeutic target.

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