Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers

Lee, Soo‐Chin; Shimasaki, Noriko; Lim, Joline Si Jing; Wong, Andrea Li‐Ann; Yadav, Kritika; Yong, Wei Peng; Tan, Lip Kun; Koh, Liang Piu; Poon, Michelle; Tan, S. G.; Ow, Samuel Guan Wei; Bharwani, Lavina; Yap, Yoon Sim; Foo, Mabel Z.Q.; Coustan‐Smith, Elaine; Sundar, Raghav; Tan, Hon Lyn; Chong, Wan Qin; Kumarakulasinghe, Nesaretnam Barr; Lieow, Jedidah L.M.; Koe, Priscillia; Goh, Boon Cher; Campana, Dario

doi:10.1158/1078-0432.ccr-20-0768

Cited by 43 publications

(37 citation statements)

References 38 publications

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“…Recently, adoptive NK cell therapy strategies have been explored in preclinical and clinical studies. Although adoptive transfer of autologous NK cells expanded ex vivo induced only very limited antitumor effect in patients with solid cancers, partially due to the immunosuppressed state of patients’ NK cells, a phase I clinical trial in patients with treatment-refractory HER2 + solid cancers treated with trastuzumab, bevacizumab, and autologous in vitro expanded NK cells reported preliminary antitumor activity, supporting the assessment of this approach in phase II trials ( 187 ). Alloreactive human pluripotent stem cell- or PBMC-derived NK cells have been widely investigated.…”

Section: Strategies To Revert Immune Suppression and Improve Cancer Imentioning

confidence: 94%

The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy

et al. 2021

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Breast cancer progression is a complex process controlled by genetic and epigenetic factors that coordinate the crosstalk between tumor cells and the components of tumor microenvironment (TME). Among those, the immune cells play a dual role during cancer onset and progression, as they can protect from tumor progression by killing immunogenic neoplastic cells, but in the meanwhile can also shape tumor immunogenicity, contributing to tumor escape. The complex interplay between cancer and the immune TME influences the outcome of immunotherapy and of many other anti-cancer therapies. Herein, we present an updated view of the pro- and anti-tumor activities of the main immune cell populations present in breast TME, such as T and NK cells, myeloid cells, innate lymphoid cells, mast cells and eosinophils, and of the underlying cytokine-, cell–cell contact- and microvesicle-based mechanisms. Moreover, current and novel therapeutic options that can revert the immunosuppressive activity of breast TME will be discussed. To this end, clinical trials assessing the efficacy of CAR-T and CAR-NK cells, cancer vaccination, immunogenic cell death-inducing chemotherapy, DNA methyl transferase and histone deacetylase inhibitors, cytokines or their inhibitors and other immunotherapies in breast cancer patients will be reviewed. The knowledge of the complex interplay that elapses between tumor and immune cells, and of the experimental therapies targeting it, would help to develop new combination treatments able to overcome tumor immune evasion mechanisms and optimize clinical benefit of current immunotherapies.

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Section: Strategies To Revert Immune Suppression and Improve Cancer Imentioning

confidence: 94%

The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy

et al. 2021

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“…NK cells express CD16 (FcRIII receptor), which is key to ADCC. Thus, among the studies being performed, there is a phase I clinical trial (NCT02030561) administering NK cells after trastuzumab (anti-HER2) treatment [32]. Autologous NK cells were expanded with K562-mb15-41BBL artificial antigen presenting cells for 10 days.…”

Section: Use Of Nk Cells In Combination With Monoclonal Antibodiesmentioning

confidence: 99%

“…In total, 66.6% of patients achieved SD for >6 months and 11% accomplished PR. The results obtained set the basis for a future phase II trial with 20 patients [32]. Another clinical study, analyzed the combination of NK cells with cetuximab (anti-EGFR) in 54 patients with advanced non-small cell lung cancer.…”

Section: Use Of Nk Cells In Combination With Monoclonal Antibodiesmentioning

confidence: 99%

Natural Killer Cells in Immunotherapy: Are We Nearly There?

Bachiller

Battram

Perez-Amill

et al. 2020

Cancers

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Natural killer (NK) cells are potent anti-tumor and anti-microbial cells of our innate immune system. They are equipped with a vast array of receptors that recognize tumor cells and other pathogens. The innate immune activity of NK cells develops faster than the adaptive one performed by T cells, and studies suggest an important immunoregulatory role for each population against the other. The association, observed in acute myeloid leukemia patients receiving haploidentical killer-immunoglobulin-like-receptor-mismatched NK cells, with induction of complete remission was the determinant to begin an increasing number of clinical studies administering NK cells for the treatment of cancer patients. Unfortunately, even though transfused NK cells demonstrated safety, their observed efficacy was poor. In recent years, novel studies have emerged, combining NK cells with other immunotherapeutic agents, such as monoclonal antibodies, which might improve clinical efficacy. Moreover, genetically-modified NK cells aimed at arming NK cells with better efficacy and persistence have appeared as another option. Here, we review novel pre-clinical and clinical studies published in the last five years administering NK cells as a monotherapy and combined with other agents, and we also review chimeric antigen receptor-modified NK cells for the treatment of cancer patients. We then describe studies regarding the role of NK cells as anti-microbial effectors, as lessons that we could learn and apply in immunotherapy applications of NK cells; these studies highlight an important immunoregulatory role performed between T cells and NK cells that should be considered when designing immunotherapeutic strategies. Lastly, we highlight novel strategies that could be combined with NK cell immunotherapy to improve their targeting, activity, and persistence.

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“…However, this may be augmented by combining NK cells with monoclonal antibody therapy thus targeting the ADCC function of NK cells, or by genetically modifying NK cells to express chimeric antigen receptors (CAR-NK cells). Both these strategies have reached clinical trials (114,115). Encouragingly the use of CD19-transduced CAR-NK cells did not result in the increase in cytokine levels associated with the systemic toxicity of CAR-T cell therapies.…”

Section: Enhancing Nk Cell Frequency and Functionmentioning

confidence: 99%

“…The infusion of NK cells has also been successful in patients with refractory acute myeloid leukaemia achieving remission in one third of patients (113). A recent phase I trial investigating the use of NK-cell therapy in combination with trastuzumab in HER2-positive cancer patients demonstrated that the therapy was well tolerated and that target engagement and anti-tumour activity was seen in the patients (115). CAR-NK cell infusion is also an exciting and promising therapy for cancer patients with a recent phase I and II trial showing that the majority (8 out of 11) patients responded to the treatment, of which 7 patients had complete disease remission (114).…”

Section: Combination Of Gmp Nk Infusion and Check Point Inhibitors In Hccmentioning

confidence: 99%

Natural Killer Cells and Regulatory T Cells Cross Talk in Hepatocellular Carcinoma: Exploring Therapeutic Options for the Next Decade

Bozward

Warricker

et al. 2021

Front. Immunol.

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Despite major advances in immunotherapy, hepatocellular carcinoma (HCC) remains a challenging target. Natural Killer (NK) cells are crucial components of the anti-HCC immune response, which can be manipulated for immunotherapeutic benefit as primary targets, modulators of the tumour microenvironment and in synchronising with tumour antigen specific effector CD8 cells for tumour clearance. Regulatory T cells shape the anti-tumour response from effector T cells via multiple suppressive mechanisms. Future research is needed to address the development of novel NK cell-targeted immunotherapy and on restraining Treg frequency and function in HCC. We have now entered a new era of anti-cancer treatment using checkpoint inhibitor (CPI)-based strategies. Combining GMP-NK cell immunotherapy to enhance the frequency of NK cells with CPI targeting both NK and CD8 T cells to release co-inhibitory receptors and enhance the cells anti-tumour immunity of HCC would be an attractive therapeutic option in the treatment of HCC. These therapeutic approaches should now be complemented by the application of genomic, proteomic and metabolomic approaches to understanding the microenvironment of HCC which, together with deep immune profiling of peripheral blood and HCC tissue before and during treatment, will provide the much-needed personalised medicine approach required to improve clinical outcomes for patients with HCC.

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Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers

Cited by 43 publications

References 38 publications

The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy

The Crosstalk Between Tumor Cells and the Immune Microenvironment in Breast Cancer: Implications for Immunotherapy

Natural Killer Cells in Immunotherapy: Are We Nearly There?

Natural Killer Cells and Regulatory T Cells Cross Talk in Hepatocellular Carcinoma: Exploring Therapeutic Options for the Next Decade

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