NK cells as adoptive cellular therapy for hematological malignancies: Advantages and hurdles

2020 ◽  
Vol 57 (4) ◽  
pp. 175-184
Author(s):  
Simona Caruso ◽  
Biagio De Angelis ◽  
Simona Carlomagno ◽  
Francesca Del Bufalo ◽  
Simona Sivori ◽  
...  
Keyword(s):  
Nk Cells ◽  
Hematological Malignancies ◽  
Cellular Therapy ◽  
Adoptive Cellular Therapy

scholarly journals Using Expanded Natural Killer Cells as Therapy for Invasive Aspergillosis

2020 ◽  
Vol 6 (4) ◽  
pp. 231
Author(s):  
Win Mar Soe ◽  
Joan Hui Juan Lim ◽  
David L. Williams ◽  
Jessamine Geraldine Goh ◽  
Zhaohong Tan ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Nk Cells ◽  
Fungicidal Activity ◽  
Cellular Therapy ◽  
Nk Cell ◽  
Adjunctive Treatment ◽  
Fungal Treatment ◽  
Adoptive Cellular Therapy

Invasive aspergillosis (IA) is a major opportunistic fungal infection in patients with haematological malignancies. Morbidity and mortality rates are high despite anti-fungal treatment, as the compromised status of immune system prevents the host from responding optimally to conventional therapy. This raises the consideration for immunotherapy as an adjunctive treatment. In this study, we evaluated the utility of expanded human NK cells as treatment against Aspergillus fumigatus infection in vitro and in vivo. The NK cells were expanded and activated by K562 cells genetically modified to express 4-1BB ligand and membrane-bound interleukin-15 (K562-41BBL-mbIL-15) as feeders. The efficacy of these cells was investigated in A. fumigatus killing assays in vitro and as adoptive cellular therapy in vivo. The expanded NK cells possessed potent killing activity at low effector-to-target ratio of 2:1. Fungicidal activity was morphotypal-dependent and most efficacious against A. fumigatus conidia. Fungicidal activity was mediated by dectin-1 receptors on the expanded NK cells leading to augmented release of perforin, resulting in enhanced direct cytolysis. In an immunocompromised mice pulmonary aspergillosis model, we showed that NK cell treatment significantly reduced fungal burden, hence demonstrating the translational potential of expanded NK cells as adjunctive therapy against IA in immunocompromised patients.

scholarly journals Hypoxia-Driven HIF-1α Activation Reprograms Pre-Activated NK Cells towards Highly Potent Effector Phenotypes via ERK/STAT3 Pathways

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1904
Author(s):  
Seon Ah Lim ◽  
Yunwon Moon ◽  
Min Hwa Shin ◽  
Tae-Jin Kim ◽  
Sehyun Chae ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Nk Cells ◽  
Target Genes ◽  
Cellular Therapy ◽  
Nk Cell ◽  
Metabolic Reprogramming ◽  
Hypoxic Exposure ◽  
Adoptive Cellular Therapy ◽  
Network Analyses ◽  
Potent Effector

NK cells are the predominant innate lymphocyte subsets specialized to kill malignant tumor cells. In patients with advanced cancer, hypoxic stress shapes NK cells toward tumor-resistant and immunosuppressive phenotypes, hence a strategy to restore NK function is critical for successful tumor immunotherapy. Here, we present evidence that pre-activation and subsequent HIF-1α-dependent metabolic shift of NK cells from oxidative phosphorylation into glycolysis are keys to overcome hypoxia-mediated impairment in NK cell survival, proliferation, and tumor cytotoxicity. Specifically, exposing NK cells to 7–9 days of normoxic culture followed by a pO2 of 1.5% hypoxia led to a highly potent effector phenotype via HIF-1α stabilization and upregulation of its target genes, BNIP3, PDK1, VEGF, PKM2, and LDHA. RNA sequencing and network analyses revealed that concomitant reduction of p21/p53 apoptotic pathways along with upregulation of cell cycle-promoting genes, CCNE1, CDC6, CDC20, and downregulation of cell cycle-arrest genes, CDKN1A, GADD45A, and MDM2 were accountable for superior expansion of NK cells via ERK/STAT3 activation. Furthermore, HIF-1α-dependent upregulation of the NKp44 receptor in hypoxia-exposed NK cells resulted in increased killing against K562, CEM, and A375 tumor targets both in-vitro and in-vivo tumor clearance assays. Therefore, hypoxic exposure on pre-activated proliferating NK cells triggered HIF-1α-dependent pathways to initiate coordinated regulation of cell cycle, apoptosis, and cytotoxicity at the global gene transcription level. Our results uncover a previously unidentified role of HIF-1α-mediated metabolic reprogramming that can reverse impaired NK effector phenotypes to generate requisite numbers of functionally robust NK cells for adoptive cellular therapy for clinical evaluation.

scholarly journals IMMU-13. MECHANISMS OF IMMUNOLOGICAL ESCAPE DURING ADOPTIVE CELLULAR THERAPY IN HIGH GRADE GLIOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi121-vi122
Author(s):  
Tyler Wildes ◽  
Kyle Dyson ◽  
Connor Francis ◽  
Brandon Wummer ◽  
Changlin Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Median Survival ◽  
Tumor Antigens ◽  
Cellular Therapy ◽  
Tumor Escape ◽  
Adoptive Cellular Therapy ◽  
Primary Tumors ◽  
Immunogenic Tumor ◽  
Escape Variant

Abstract INTRODUCTION Immunotherapy is remarkably effective, yet tumor escape is common. Herein, we investigated tumor escape after adoptive cellular therapy (ACT) in intractable glioma models. These studies revealed multiple mechanisms of escape including a shift in immunogenic tumor antigens, downregulation of MHC-I, and upregulation of checkpoint molecules. Despite these changes, we HYPOTHESIZED that a new population of escape variant-specific polyclonal T cells could be generated to target immune-escaped tumors through using tumor escape variant RNA. METHODS We studied KR158B-luc glioma-bearing mice during treatment with ACT with polyclonal tumor-specific T cells. We tested the immunogenicity of primary and escaped tumors using T cell restimulation assays. We used flow cytometry and RNA profiling of whole tumors to further define escape mechanisms. To treat immune-escaped tumors, we generated escape variant-specific T cells through the use of escape variant total tumor RNA and administered these cells as ACT. RESULTS Escape mechanisms included a shift in immunogenic tumor antigens, downregulation of major histocompatibility complex (MHC) class I by 50%, and upregulation of checkpoint molecules. This included activated T cells and NK cells from tumor-draining lymph nodes expressing 50% and 30% PD-1 after ACT. Importantly, polyclonal T cells specific for escape variants displayed greater recognition of escaped tumors than primary tumors. When administered as ACT, these T cells prolonged median survival of escape variant-bearing mice by 60% (24 to 33 days, p=.0003). The rational combination of ACT with PD-1 blockade prolonged median survival of escape variant glioma-bearing mice by 110% and was dependent upon NK cells and T cells as determined by cell depletion experiments. To prevent escape from primary tumors, we combined ACT with PD-1 blockade to yield 71% long-term cures in KR158B-luc-bearing mice. CONCLUSIONS These findings suggest that the immune landscape of brain tumors is markedly different post-immunotherapy yet can still be targeted with immunotherapy.

Chimeric antigen receptor T in the treatment of multiple myeloma – state of the art and future directions

2020 ◽  
Vol 51 (3) ◽  
pp. 120-124
Author(s):  
Dominik Dytfeld
Keyword(s):  
Multiple Myeloma ◽  
Chimeric Antigen Receptor ◽  
Cellular Therapy ◽  
New Technology ◽  
Phase 1 ◽  
Antigen Receptor ◽  
New Drugs ◽  
Adoptive Cellular Therapy ◽  
B Cell Maturation ◽  
Complexity Cost

AbstractIn spite of the introduction of several new drugs in the last 10 years, multiple myeloma (MM) remains incurable. Thus, an adoptive cellular therapy using chimeric antigen receptor T (CART), a strategy to increase the frequency of tumor-directed and functionally active T cells targeting antigens present on the cancer cell, might change the treatment in MM as it did in lymphoma and ALL. There are several targets for CART therapy in MM on different levels of development, which are discussed in the manuscript. B-cell maturation antigen (BCMA) being tested in the studies of phase 1–2 is the most promising, but so far CART has not been approved in the cure of MM and remains an experimental approach. The hematological society is facing a new technology which with its potential ability to cure MM, in spite of its complexity, cost, and toxicity, will definitely and soon change the landscape of myeloma in Europe and world-wide.

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.

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