Overcome the Impairment of NK Cells for Icon and Antibody Immunotherapy of Cancer

Hu, Zhiwei

doi:10.4236/jibtva.2013.21001

Cited by 8 publications

(17 citation statements)

References 89 publications

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“…Which is known is that blood-born cancer cells use different mechanisms for immune escape (25,26), e.g., by inducing NK cell dysfunction (27). This mechanism has also been observed in a variety of solid tumor patients (17).…”

Section: Nk Cells In Clinics: the Problemsmentioning

confidence: 96%

“…This led to the development of IPH2101, a killer inhibitory receptors (KIRs)/KIRL blocking antibody (Ab) (15), or monalizumab, a humanized anti-NKG2A Ab (16). This approach has the inconvenience that in cancer patients NK cells are hyporeactive (11,12,17). Moreover, new therapies such as NK cell-based therapies are usually tested on patients with advance clinical Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; AML, acute myeloid leukemia; B-CLL, B-cell chronic lymphocytic leukemia; B-NHL, B-cell non-Hodgkin's lymphoma; BCL, B-cell lymphoma; DLBCL, Diffuse large Bcell lymphoma; EBV, Epstein-Barr virus; EGFR, epidermal growth factor receptor; e-NK, expanded NK cells; FL, follicular lymphoma; GMP, good manufacturing practices; GvHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplantation; LEN, lenalidomide; mAbs, monoclonal antibodies; NCRs, natural cytotoxicity receptors; NK cells, natural killer cells; OBZ, obinutuzumab; PFS, progression-free survival; RTX, rituximab; UCB, umbilical cord blood; UCBT, umbilical cord blood transplantation.…”

Section: Nk Cells In Clinics: the Problemsmentioning

confidence: 99%

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Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

et al. 2020

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The innate lymphocyte lineage natural killer (NK) is now the target of multiple clinical applications, although none has received an agreement from any regulatory agency yet. Transplant of naïve NK cells has not proven efficient enough in the vast majority of clinical trials. Hence, new protocols wish to improve their medical use by producing them from stem cells and/or modifying them by genetic engineering. These techniques have given interesting results but these improvements often hide that natural killers are mainly that: natural. We discuss here different ways to take advantage of NK physiology to improve their clinical activity without the need of additional modifications except for in vitro activation and expansion and allograft in patients. Some of these tactics include combination with monoclonal antibodies (mAb), drugs that change metabolism and engraftment of specific NK subsets with particular activity. Finally, we propose to use specific NK cell subsets found in certain patients that show increase activity against a specific disease, including the use of NK cells derived from patients.

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Section: Nk Cells In Clinics: the Problemsmentioning

confidence: 96%

Section: Nk Cells In Clinics: the Problemsmentioning

confidence: 99%

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

et al. 2020

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“…What can we offer for the majority of patients if their tumors are negative for expression of these checkpoint molecules, or are too few or lack of infiltration of CD4, CD8 T cells and NK cells, or even are positive for the expression of checkpoint molecules but are still resistant to current blockade therapy? In fact, immune impairment is commonly observed in cancer patients, such as impairment of T cells (19) and NK cells (20). To achieve an optimal clinical outcome for cancer patients, we believe that the future of immune checkpoint blockade therapy, or in general, cancer immunotherapy, should be towards personalized combination therapy with existing approaches, such as: therapeutic antibodies, antibody-drug conjugates, immune checkpoint blockades, CAR-T and NK cells, DCs, vaccines, oncolytic viruses, cytokines and/or depletion of immune suppressor cells like myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), tumor-associated macrophages (TAM), etc.…”

Section: Editorialmentioning

confidence: 99%

The future of immune checkpoint blockade immunotherapy: towards personalized therapy or towards combination therapy

Hu¹

2017

J. Thorac. Dis.

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“…Our lab recently improved it to a second-generation ICON (called L-ICON or L-ICON1) by removing the procoagulant heavy chain of fVII from ICON, resulting in a >50% reduction in molecular mass (92.5 kDa), complete depletion of procoagulant activity 14 and higher binding activity and antibody-dependent cell-mediated cytotoxicity (ADCC) to TNBC cells than the original ICON. It is well documented that NK cells are crucial as CD16+ ADCC effector cells for the efficacy of antibody immunotherapy using ICON 36 , L-ICON 14 or other therapeutic antibody 38 . However, NK cells are often impaired in cancer patients 38 , including patients with breast cancer 39,40 .…”

mentioning

confidence: 99%

“…It is well documented that NK cells are crucial as CD16+ ADCC effector cells for the efficacy of antibody immunotherapy using ICON 36 , L-ICON 14 or other therapeutic antibody 38 . However, NK cells are often impaired in cancer patients 38 , including patients with breast cancer 39,40 . NK impairment in cancer patients could reduce the therapeutic efficacy of ICON, L-ICON and antibody immunotherapy.…”

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confidence: 99%

Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer

2020

Sci Rep

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Triple-negative breast cancer (TNBC), representing ~15% of globally diagnosed breast cancer, is typically an incurable malignancy due to the lack of targetable surface targets for development of effective therapy. To address the unmet need for TNBC treatment, we recently determined that tissue factor (TF) is a useful surface target in 50-85% of patients with TNBC and developed a secondgeneration TF-targeting antibody-like immunoconjugate (called L-ICON) for preclinical treatment of TNBC. Using the chimeric antigen receptor (CAR) approach, here we develop and test TF-targeting CARengineered natural killer (TF-CAR-NK) cells that co-express CD16, the Fc receptor (FcγIII) to mediate antibody-dependent cellular toxicity (ADCC), for a preclinical assessment of immunotherapy of TNBC using TF-CAR-NK cell as single agent therapy and in combination with L-ICON. Our preclinical results demonstrate that TF-CAR-NK cells alone could kill TNBC cells and its efficacy was enhanced with L-ICON ADCC in vitro. Moreover, TF-CAR-NK cells were effective in vivo for the treatment of tnBc in cell lineand patient's tumor-derived xenograft mouse models. Thus, this study established the proof of concept of targeting TF as a new target in CAR-NK immunotherapy for effective treatment of TNBC and may warrant further preclinical study and potentially future investigation in TNBC patients.The adoptive transfer of chimeric antigen receptor (CAR)-expressing T and natural killer (NK) cells represents a novel cancer immunotherapy approach. The concept of the CAR is based upon the idea of expressing novel receptors on the T or NK cell surface that would enable the T and NK cell to identify corresponding antigens on the surface of a target cell. The basic CAR construct consists of an extracellular antigen-recognition domain, usually single-chain antibody variable fragments (scFv), attached to an extracellular spacer domain, a transmembrane domain of CD28 and a signaling cytoplasmic domain such as 4-1BB (CD137), OX40 (CD134), DAP10, ICOS and CD3zeta chain (CD3ζ). The most advanced application is the use of CAR-T cells targeting CD19, a surface antigen on B cell malignancies, which has demonstrated antitumor efficacy in patients with these cancers 1 . However, early-phase clinical trials of CAR T therapy also showed that this treatment is frequently associated with side effects 1 , some even causing life-threatening toxicity 2 , partly due to the fact that current CAR targets are expressed by both the malignant cells and normal cells, such as CD19, which is also expressed by normal B cells throughout the B cell lineage 1 . Also, one of the major challenges in CAR therapy is the heterogeneity of tumor antigens, for instance, antigen loss or low antigen density on the cancer cells 3 . To overcome these challenges, it would be ideal to develop CAR T or CAR NK cells that could target a surface molecule that is commonly yet selectively expressed by several major tumor compartments, including but not limited to, the cancer cell, cancer stem cell (CSC) and tum...

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Overcome the Impairment of NK Cells for Icon and Antibody Immunotherapy of Cancer

Cited by 8 publications

References 89 publications

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

The future of immune checkpoint blockade immunotherapy: towards personalized therapy or towards combination therapy

Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer

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