scholarly journals CAR-NK Cells in the Treatment of Solid Tumors

2021 ◽  
Vol 22 (11) ◽  
pp. 5899
Author(s):  
Ewa Wrona ◽  
Maciej Borowiec ◽  
Piotr Potemski
Keyword(s):  
Nk Cells ◽  
Solid Tumors ◽  
Hematological Malignancies ◽  
Toxicity Profile ◽  
Multiple Sources ◽  
Eligibility Criteria ◽  
Hematological Neoplasms ◽  
Current State ◽  
Car T ◽  
The Cost

CAR-T (chimeric antigen receptor T) cells have emerged as a milestone in the treatment of patients with refractory B-cell neoplasms. However, despite having unprecedented efficacy against hematological malignancies, the treatment is far from flawless. Its greatest drawbacks arise from a challenging and expensive production process, strict patient eligibility criteria and serious toxicity profile. One possible solution, supported by robust research, is the replacement of T lymphocytes with NK cells for CAR expression. NK cells seem to be an attractive vehicle for CAR expression as they can be derived from multiple sources and safely infused regardless of donor–patient matching, which greatly reduces the cost of the treatment. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have activity against non-hematological neoplasms. Here, we present a thorough overview of the current state of knowledge regarding the use of CAR-NK cells in treating various solid tumors.

scholarly journals 150 GAIA-102: a new class off-the-shelf allogeneic NK-like cells that can eliminate solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A163-A163
Author(s):  
Yui Harada ◽  
Yoshikazu Yonemitsu
Keyword(s):  
Nk Cells ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Adoptive Immunotherapy ◽  
Nk Cell ◽  
Peritoneal Dissemination ◽  
Checkpoint Inhibitors ◽  
Antitumor Effects ◽  
Car T

BackgroundCancer immunotherapy has been established as a new therapeutic category since the recent success of immune checkpoint inhibitors and a type of adoptive immunotherapy, namely chimeric antigen receptor-modified T cells (CAR-T). Although CAR-T demonstrated impressive clinical results, serious adverse effects (cytokine storm and on-target off-tumor toxicity) and undefined efficacy on solid tumors are important issues to be solved. We’ve developed a cutting-edge, simple, and feeder-free method to generate highly activated and expanded human NK cells from peripheral blood (US9404083, PCT/JP2019/012744, PCT/JP2020/012386), and have been conducting further investigation why our new type of NK cells, named as GAIA-102, are so effective to kill malignant cells.MethodsCryopreserved PBMCs purchased from vendors were mixed and processed by using LOVO and CliniMACS® Prodigy (automated/closed systems). CD3+ and CD34+ cells were depleted, and the cells were cultured with high concentration of hIL-2 and 5% UltraGRO® for 14 days in our original closed system. Then, we confirmed the expression of surface markers, CD107a mobilization and cell-mediated cytotoxicity against various tumor cells and normal cells with or without monoclonal antibody drugs in vitro and antitumor effects against peritoneal dissemination model using SKOV3 in vivo.ResultsImportantly, we’ve found that our GAIA-102 exhibited CD3-/CD56bright/CD57- immature phenotype that could kill various tumor cells efficiently from various origins, including Raji cells that was highly resistant to NK cell killing. More importantly, massive accumulation, retention, infiltration and sphere destruction by GAIA-102 were affected neither by myeloid-derived suppressor cells nor regulatory T-lymphocytes. GAIA-102 was also effective in vivo to murine model of peritoneal dissemination of human ovarian cancer; thus, these findings indicate that GAIA-102 has a potential to be an ‘upward compatible’ modality over CAR-T strategy, and would be a new and promising candidate for adoptive immunotherapy against solid tumors.ConclusionsWe now just started GMP/GCTP production of this new and powerful NK cells and first-in-human clinical trials in use of GAIA-102 will be initiated on 2021.Ethics ApprovalThe animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee of Kyushu University (approval nos. A30-234-0 and A30-359-0).

scholarly journals CAR T cell therapy in solid tumors: a short review

2021 ◽  
Author(s):  
Öykü Umut ◽  
Adrian Gottschlich ◽  
Stefan Endres ◽  
Sebastian Kobold
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Hematological Malignancies ◽  
Short Review ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Solid Malignancies ◽  
Car T

SummaryChimeric antigen receptor (CAR) T cell therapy has been established in the treatment of hematological malignancies. However, in solid tumors its efficacy remains limited. The aim of this article is to give an overview of the field of cell therapy itself, to introduce the underlying concepts of CAR T cell-based treatment approaches and to address its limitations in advancing the treatment for solid malignancies.

scholarly journals The tumor vasculature an attractive CAR T cell target in solid tumors

Angiogenesis ◽  
2019 ◽  
Vol 22 (4) ◽  
pp. 473-475 ◽  
Author(s):  
Parvin Akbari ◽  
Elisabeth J. M. Huijbers ◽  
Maria Themeli ◽  
Arjan W. Griffioen ◽  
Judy R. van Beijnum
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Hematological Malignancies ◽  
Tumor Vasculature ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract T cells armed with a chimeric antigen receptor, CAR T cells, have shown extraordinary activity against certain B lymphocyte malignancies, when targeted towards the CD19 B cell surface marker. These results have led to the regulatory approval of two CAR T cell approaches. Translation of this result to the solid tumor setting has been problematic until now. A number of differences between liquid and solid tumors are likely to cause this discrepancy. The main ones of these are undoubtedly the uncomplicated availability of the target cell within the blood compartment and the abundant expression of the target molecule on the cancerous cells in the case of hematological malignancies. Targets expressed by solid tumor cells are hard to engage due to the non-adhesive and abnormal vasculature, while conditions in the tumor microenvironment can be extremely immunosuppressive. Targets in the tumor vasculature are readily reachable by CAR T cells and reside outside the immunosuppressive tumor microenvironment. It is therefore hypothesized that targeting CAR T cells towards the tumor vasculature of solid tumors may share the excellent effects of CAR T cell therapy with that against hematological malignancies. A few reports have shown promising results. Suggestions are provided for further improvement.

scholarly journals Understanding and Targeting the Wnt/β-Catenin Signaling Pathway in Chronic Leukemia

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
S. Thanendrarajan ◽  
Y. Kim ◽  
I. G. H. Schmidt-Wolf
Keyword(s):  
B Cell ◽  
Signaling Pathway ◽  
Solid Tumors ◽  
Wnt Pathway ◽  
Hematological Malignancies ◽  
Therapeutic Options ◽  
Special Focus ◽  
Chronic Leukemia ◽  
Current State ◽  
Experimental Approaches

It has been revealed that the Wnt/β-catenin signaling pathway plays an important role in the development of solid tumors and hematological malignancies, particularly in B-cell neoplasia and leukemia. In the last decade there have been made experimental approaches targeting the Wnt pathway in chronic leukemia. In this paper we provide an overview about the current state of knowledge regarding the Wnt/β-catenin signaling pathway in chronic leukemia with special focus on therapeutic options and strategies.

scholarly journals Synchronous Presentation of Two Extranodal Lymphomas: Follicular Lymphoma and Extranodal Marginal Zone Lymphoma of the Mucosa-Associated Lymphoid Tissue (MALToma)

2018 ◽  
Vol 49 (1) ◽  
pp. 42-45
Author(s):  
Yelda Dere ◽  
Volkan Karakuş ◽  
Özcan Dere ◽  
Nazan Özsan
Keyword(s):  
Follicular Lymphoma ◽  
Solid Tumors ◽  
Lymphoid Tissue ◽  
Hematological Malignancies ◽  
Marginal Zone ◽  
Treatment Resistance ◽  
Marginal Zone Lymphoma ◽  
Hematological Neoplasms ◽  
Synchronous Malignancies ◽  
Extranodal Lymphomas

AbstractSynchronous malignancies are rare conditions in oncology practices, generally seen as solid tumors with hematological neoplasms. However, occurrence of two different hematological malignancies in the same patient is extremely rare. Two primary malignancies should be considered especially in patients with extraordinary presentations and treatment resistance.

scholarly journals NK Cells Expressing a Chimeric Activating Receptor Eliminate MDSCs and Rescue Impaired CAR-T Cell Activity against Solid Tumors

2019 ◽  
Vol 7 (3) ◽  
pp. 363-375 ◽  
Author(s):  
Robin Parihar ◽  
Charlotte Rivas ◽  
Mai Huynh ◽  
Bilal Omer ◽  
Natalia Lapteva ◽  
...  
Keyword(s):  
T Cell ◽  
Nk Cells ◽  
Solid Tumors ◽  
Cell Activity ◽  
Car T Cell ◽  
Car T ◽  
Activating Receptor

scholarly journals Combination Therapy with EpCAM-CAR-NK-92 Cells and Regorafenib against Human Colorectal Cancer Models

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Qing Zhang ◽  
Haixu Zhang ◽  
Jiage Ding ◽  
Hongyan Liu ◽  
Huizhong Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Therapy ◽  
Nk Cells ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Therapeutic Efficacy ◽  
Synergistic Effects ◽  
Human Colorectal Cancer ◽  
Car T

Adoptive chimeric antigen receptor-modified T or NK cells (CAR-T or CAR-NK) offer new options for cancer treatment. CAR-T therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. However, their therapeutic efficacy against solid tumors is limited. New regimens, including combinations with chemical drugs, need to be studied to enhance the therapeutic efficacy of CAR-T or NK cells for solid tumors. An epithelial cell adhesion molecule- (EpCAM-) specific second-generation CAR was constructed and transduced into NK-92 cells by lentiviral vectors. Immune effects, including cytokine release and cytotoxicity of the CAR-NK-92 cells against EpCAM-positive colon cancer cells, were evaluated in vitro. Synergistic effects of regorafenib and CAR-NK-92 cells were analyzed in a mouse model with human colorectal cancer xenografts. The CAR-NK-92 cells can specifically recognize EpCAM-positive colorectal cancer cells and release cytokines, including IFN-γ, perforin, and granzyme B, and show specific cytotoxicity in vitro. The growth suppression efficacy of combination therapy with regorafenib and CAR-NK-92 cells on established EpCAM-positive tumor xenografts was more significant than that of monotherapy with CAR-NK-92 cells or regorafenib. Our results provided a novel strategy to treat colorectal cancer and enhance the therapeutic efficacy of CAR-modified immune effector cells for solid tumors.

scholarly journals Pushing Past the Blockade: Advancements in T Cell-Based Cancer Immunotherapies

2021 ◽  
Vol 12 ◽  
Author(s):  
Jessica Waibl Polania ◽  
Emily C. Lerner ◽  
Daniel S. Wilkinson ◽  
Alexandra Hoyt-Miggelbrink ◽  
Peter E. Fecci
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Hematological Malignancies ◽  
Cell Function ◽  
Checkpoint Inhibition ◽  
Considerable Success ◽  
Car T ◽  
Immunosuppressive Tumor Microenvironment ◽  
Cancer Immunotherapies

Successful cancer immunotherapies rely on a replete and functional immune compartment. Within the immune compartment, T cells are often the effector arm of immune-based strategies due to their potent cytotoxic capabilities. However, many tumors have evolved a variety of mechanisms to evade T cell-mediated killing. Thus, while many T cell-based immunotherapies, such as immune checkpoint inhibition (ICI) and chimeric antigen receptor (CAR) T cells, have achieved considerable success in some solid cancers and hematological malignancies, these therapies often fail in solid tumors due to tumor-imposed T cell dysfunctions. These dysfunctional mechanisms broadly include reduced T cell access into and identification of tumors, as well as an overall immunosuppressive tumor microenvironment that elicits T cell exhaustion. Therefore, novel, rational approaches are necessary to overcome the barriers to T cell function elicited by solid tumors. In this review, we will provide an overview of conventional immunotherapeutic strategies and the various barriers to T cell anti-tumor function encountered in solid tumors that lead to resistance. We will also explore a sampling of emerging strategies specifically aimed to bypass these tumor-imposed boundaries to T cell-based immunotherapies.

scholarly journals Co-expression of IL-7 and PH20 Promote anti-GPC3 CAR-T Tumor Suppressor Activity in Vivo and in Vitro

2020 ◽  
Author(s):  
Qian Liu ◽  
Cixiao Wang ◽  
Zeyou Jiang ◽  
Su-yang Yue
Keyword(s):  
T Cells ◽  
Solid Tumors ◽  
Hematological Malignancies ◽  
Tumor Tissue ◽  
Suppressor Activity ◽  
Car T Cells ◽  
Car T ◽  
Tumor Suppressor Activity

Abstract While CAR-T therapy has successfully treated hematological malignancies, it has proved sub-optimal for solid tumors. The main limitation is the inability of CAR-T cells to infiltrate and then proliferate within tumors. In this study, we co-expressed IL-7 and PH20, a type of hyaluronidase, with CAR targeting GPC3 (G3CAR-7×20) to address these issues. We found (G3CAR-7×20) exhibited better proliferation in vivo and in vitro than G3CAR, reduced the level of apoptosis after stimulation by tumor cells, and maintained the memory phenotype of CAR-T cells. G3CAR-7×20 also increased the ability of CAR-T cells to infiltrate tumor tissue. G3CAR-7×20 may significantly enhance the efficacy of CAR-T cells in solid tumors.

scholarly journals Revisiting NTRKs as an emerging oncogene in hematological malignancies

Leukemia ◽  
2019 ◽  
Vol 33 (11) ◽  
pp. 2563-2574 ◽  
Author(s):  
Sunil K. Joshi ◽  
Monika A. Davare ◽  
Brian J. Druker ◽  
Cristina E. Tognon
Keyword(s):  
Solid Tumors ◽  
Hematological Malignancies ◽  
Leukemia Cell ◽  
Hematologic Malignancies ◽  
Human Leukemia ◽  
Low Frequencies ◽  
Sequencing Technologies ◽  
Current State ◽  
Leukemia Cell Lines ◽  
Trk Inhibitors

Abstract NTRK fusions are dominant oncogenic drivers found in rare solid tumors. These fusions have also been identified in more common cancers, such as lung and colorectal carcinomas, albeit at low frequencies. Patients harboring these fusions demonstrate significant clinical response to inhibitors such as entrectinib and larotrectinib. Although current trials have focused entirely on solid tumors, there is evidence supporting the use of these drugs for patients with leukemia. To assess the broader applicability for Trk inhibitors in hematological malignancies, this review describes the current state of knowledge about alterations in the NTRK family in these disorders. We present these findings in relation to the discovery and therapeutic targeting of BCR–ABL1 in chronic myeloid leukemia. The advent of deep sequencing technologies has shown that NTRK fusions and somatic mutations are present in a variety of hematologic malignancies. Efficacy of Trk inhibitors has been demonstrated in NTRK-fusion positive human leukemia cell lines and patient-derived xenograft studies, highlighting the potential clinical utility of these inhibitors for a subset of leukemia patients.

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