Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas

Kruschinski, Anna; Moosmann, Andreas; Poschke, Isabel; Norell, Håkan; Chmielewski, Markus; Seliger, Barbara; Kiessling, Rolf; Blankenstein, Thomas; Abken, Hinrich; Charo, Jehad

doi:10.1073/pnas.0804788105

Cited by 177 publications

(128 citation statements)

References 42 publications

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“…However, concern has been raised about genetically modified autoreactive T cells, which might cause undesirable side effects after infusion into patients. NK cells, in contrast, do not possess TCR-like molecules that might (21,(41)(42)(43)(65)(66)(67)(68).…”

Section: Discussionmentioning

confidence: 99%

“…3 were also incubated with the bladder carcinoma cell lines RT4 and HT1376, which show endogenous expression of PSCA. *p , 0.05. edge, we treated for the first time established solid tumors with CAR-modified NK cells, whereas other groups favored mixing of NK cells and target cells prior to tumor transplantation (23,(65)(66)(67) or chose an experimental setting that most likely confronts injected tumor cells and CAR-modified NK cells in the bloodstream or lung capillaries (67). In this article, we demonstrate that treatment with YTS anti-PSCA-DAP12 NK cells resulted in a significantly delayed growth of PSCA-positive tumors when compared with tumors treated with YTS wt cells and YTS myc-DAP12 controls, respectively.…”

Section: Discussionmentioning

confidence: 99%

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DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

Töpfer

Cartellieri

Michen

et al. 2015

The Journal of Immunology

197

162

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NK cells are emerging as new effectors for immunotherapy of cancer. In particular, the genetic engraftment of chimeric Ag receptors (CARs) in NK cells is a promising strategy to redirect NK cells to otherwise NK cell–resistant tumor cells. On the basis of DNAX-activation protein 12 (DAP12), a signaling adaptor molecule involved in signal transduction of activating NK cell receptors, we generated a new type of CAR targeting the prostate stem cell Ag (PSCA). We demonstrate in this article that this CAR, designated anti–PSCA-DAP12, consisting of DAP12 fused to the anti-PSCA single-chain Ab fragment scFv(AM1) confers improved cytotoxicity to the NK cell line YTS against PSCA-positive tumor cells when compared with a CAR containing the CD3ζ signaling chain. Further analyses revealed phosphorylation of the DAP12-associated ZAP-70 kinase and IFN-γ release of CAR-engineered cells after contact with PSCA-positive target cells. YTS cells modified with DAP12 alone or with a CAR bearing a phosphorylation-defective ITAM were not activated. Notably, infused YTS cells armed with anti–PSCA-DAP12 caused delayed tumor xenograft growth and resulted in complete tumor eradication in a significant fraction of treated mice. The feasibility of the DAP12-based CAR was further tested in human primary NK cells and confers specific cytotoxicity against KIR/HLA-matched PSCA-positive tumor cells, which was further enhanced by KIR-HLA mismatches. We conclude that NK cells engineered with DAP12-based CARs are a promising tool for adoptive tumor immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

Töpfer

Cartellieri

Michen

et al. 2015

The Journal of Immunology

197

162

View full text Add to dashboard Cite

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“…Also, the majority of patients who initially respond to trastuzumab become resistant within 1 year of treatment initiation (18). Although there is a pressing need for novel therapeutic approaches, so far, few efforts were undertaken to generate HER-2-specific oncolytic viruses or lytic immune cells (19,39). Such viruses share their target with small molecule inhibitors (SMI) and, particularly, mAbs.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells

Menotti

Nicoletti

Gatta

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

126

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Oncolytic virotherapy exploits the ability of viruses to infect, replicate into, and kill tumor cells. Among the viruses that entered clinical trials are HSVs. HSVs can be engineered to become tumorspecific by deletion of selected genes or retargeting to tumorspecific receptors. A clinically relevant surface molecule is HER-2, hyperexpressed in one fourth of mammary and ovary carcinomas, and associated with high metastatic ability. As a previously undescribed strategy to generate HSV recombinants retargeted to HER-2 and detargeted from natural receptors, we replaced the Ig-folded core in the receptor-binding virion glycoprotein gD with anti-HER-2 single-chain antibody. The recombinant entered cells solely via HER-2 and lysed HER-2-positive cancer cells. Because of the high specificity, its safety profile in i.p. injected mice was very high, with a LD 50 >5 ؋ 10 8 pfu, a figure at least 10,000-fold higher than that of corresponding WT-gD carrying virus (LD 50 Ϸ 5 ؋ 10 4 pfu). When administered intratumorally to nude mice bearing HER-2-hyperexpressing human tumors, it strongly inhibited progressive tumor growth. The results provide a generally applicable strategy to engineer HSV recombinants retargeted to a wide range of receptors for which a single-chain antibody is available, and show the potential for retargeted HSV to exert target-specific inhibition of human tumor growth. Therapy with HER-2-retargeted oncolytic HSV could be effective in combined or sequential protocols with monoclonal antibodies and small inhibitors, particularly in patients resistant to HER-2-targeted therapy because of alterations in HER-2 signaling pathway, or against brain metastases inaccessible to anti-HER-2 antibodies. mammary carcinoma ͉ ovary carcinoma ͉ retarget ͉ tropism

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“…These data, as well as recent data showing the efficacy of T-cell-based CAR therapy targeting CD19 in B-cell malignancies, suggest that NK cells modified to express CARs after mRNA or viral transduction represent a therapeutic tool worthy of exploration in the clinical setting. 43,44,57,73,[76][77][78][79] The ability of CAR-expressing NK cells to home to the tumor may be a critical determinant of their efficacy in humans. As discussed previously, expanded NK cells may lack or down-regulate molecules that are critical for NK cell homing from the circulation.…”

Section: Future Directions: Engineering a Better Nk Cellmentioning

confidence: 99%

Bringing natural killer cells to the clinic: ex vivo manipulation

Childs

Berg

2013

Hematology

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Recently, there has been a substantial gain in our understanding of the role that natural killer (NK) cells play in mediating innate host immune responses against viruses and cancer. Although NK cells have long been known to be capable of killing cancer cells independently of antigen recognition, the full therapeutic potential of NK cell-based immunotherapy has yet to be realized. Here we review novel methods to activate and expand human NK cells ex vivo for adoptive transfer in humans, focusing on the important phenotypic and functional differences observed among freshly isolated, cytokine activated, and ex vivo-expanded NK populations. Natural killer cell therapy for cancer: a new hopeThe ability of natural killer (NK) cells to kill tumor cells without the need to recognize a tumor-specific antigen provides advantages over T cells and makes them appealing for investigation as effectors for immunotherapy. 1,2 There has recently been a substantial gain in our understanding of the role that NK cells play in mediating innate host immune responses against viruses and cancer. Although NK cells have long been known to be capable of killing cancer cells independently of antigen recognition, the full therapeutic potential of NK cell-based immunotherapy has yet to be realized. Here we review novel methods to activate and expand human NK cells ex vivo for adoptive transfer in humans, focusing on the important phenotypic and functional differences observed among freshly isolated, cytokine activated, and ex vivo-expanded NK populations. Ex vivo NK cell activation and expansionUnlike T cells, NK cells represent only a minor fraction of human lymphocytes. NK cells are defined by their CD3 Ϫ /CD56 ϩ phenotype, comprising 5% to 15% of circulating lymphocytes, and are commonly divided into CD56 dim CD16 ϩ (90%) and CD56 bright CD16 Ϫ (10%) subpopulations with distinct effector functions. Recently, investigators have shown that NK cell tumor cytotoxicity can be enhanced by disrupting NK cell signaling through inhibitory receptors such as KIR, PD-1, and NKG2A. 3,4 Furthermore, exposing tumors to drugs that down-regulate ligands for NK cell inhibitory receptors or up-regulate death receptors for NK cell effector molecules or ligands that bind NK cell-activating receptors can be used as a strategy to sensitize tumors to NK cell-mediated apoptosis. Recently, anti-PD-1 and anti-PD-L1 monoclonal antibodies and the immunomodulatory drug lenalidomide were shown to enhance both NK cell tumor trafficking and NK cell-mediated antibody-dependent cell-mediated cytotoxicity, and cytokine release against tumors while simultaneously suppressing regulatory T cell function. [5][6][7][8] Similarly, anti-CTLA-4 monoclonal antibodies have been shown to augment NK cell antibody-dependent cellmediated cytotoxicity and TNF␣ release against melanoma cells by Fc␥RIII (CD16) binding to antibody-bound tumor cells, as well as through regulatory T cell inactivation. 9-11 These data suggest these agents could be used in conjunction with autologous NK cell inf...

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Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas

Abstract: immunotherapy ͉ in vivo imaging ͉ tumor biology ͉ tolerance ͉ retroviral transduction

Cited by 177 publications

References 42 publications

DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

DAP12-Based Activating Chimeric Antigen Receptor for NK Cell Tumor Immunotherapy

Inhibition of human tumor growth in mice by an oncolytic herpes simplex virus designed to target solely HER-2-positive cells

Bringing natural killer cells to the clinic: ex vivo manipulation

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