IL-15 enhances the anti-tumor activity of trastuzumab against breast cancer cells but causes fatal side effects in humanized tumor mice (HTM)

Wege, Anja K.; Weber, Florian; Kroemer, Alexander; Ortmann, O.; Nimmerjahn, Falk; Brockhoff, Gero

doi:10.18632/oncotarget.13159

Cited by 24 publications

(26 citation statements)

References 48 publications

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“…Another study confirmed that chronic exposure of IL-15 induces transformation of large granular lymphocyte leukemia in vitro (76). A recent paper reported that IL-15 caused fetal side effects when administered in mice bearing humanized tumors (77). In nonhuman primates, IL-15 was known to cause considerable dose-dependent toxicity such as grade 3/4 transient neutropenia, weight loss and skin rash at higher doses (78).…”

Section: Il-15 Superagonist Toxicitymentioning

confidence: 99%

Immunobiology of the IL-15/IL-15Rα complex as an antitumor and antiviral agent

Guo

Luan

Patil

et al. 2017

Cytokine & Growth Factor Reviews

120

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Interleukin (IL)-15 is essential for natural killer (NK), NKT and memory (m) CD8+ T cell development and function, and is currently under investigation as an immunotherapeutic agent for the treatment of cancer. Recently, the creation of IL-15 superagonist by complexing IL-15 and its high affinity receptor alpha (IL-15 Rα) in solution, inspired by the natural trans-presentation of IL-15, advances the potential of IL-15-based tumor immunotherapy. IL-15 superagonist shows promising advantages over monomeric IL-15 such as sustaining high circulating concentrations due to prolonged half-life and more potently stimulating NK and CD8+ T effector lymphocytes. So far, there are three different forms of recombinant IL-15 superagonist fusion protein based on configurational modifications. Gene therapy using engineered cells co-expressing IL-15/IL-15 Rα complex for cancer treatment is also emerging. All forms have demonstrated efficacy in causing tumor regression in animal studies, which provides strong rationale for advancing IL-15 superagonist through clinical trials. To date, there are fourteen phase I/II IL-15 superagonist trials in cancer patients and one phase I trial in HIV patients. Information generated by ongoing trials regarding the toxicity and efficacy of IL-15 superagonist is awaited. Finally, we elaborate on immunotoxicity caused by IL-15 superagonist in preclinical studies and discuss important safety considerations.

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Section: Il-15 Superagonist Toxicitymentioning

confidence: 99%

Immunobiology of the IL-15/IL-15Rα complex as an antitumor and antiviral agent

Guo

Luan

Patil

et al. 2017

Cytokine & Growth Factor Reviews

120

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“…IL-15 is an essential cytokine for human NK cell homeostasis; nonetheless, early clinical assays including systemic IL-15 were withdrawn due to concurrent adverse events and dose-limiting toxicities ( 181 ). Similarly, IL-15 enhanced the antitumor activity of trastuzumab, yet causing fatal side effects in a humanized tumor mice model ( 182 ). Current research efforts include the development of cytokine variants with extended in vivo half-life and targeted action on precise lymphocyte subsets and tumor sites (i.e., engineered IL-2 “superkine,” IL-15Rα Sushi-Fc fusion protein; IL-15 tri and tetraspecific killer engagers) ( 183 – 186 ).…”

Section: Enhancing Nk Cell-mediated Adcc Through Immunotherapy In Hermentioning

confidence: 99%

Interplay between Natural Killer Cells and Anti-HER2 Antibodies: Perspectives for Breast Cancer Immunotherapy

et al. 2017

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Overexpression of the human epidermal growth factor receptor 2 (HER2) defines a subgroup of breast tumors with aggressive behavior. The addition of HER2-targeted antibodies (i.e., trastuzumab, pertuzumab) to chemotherapy significantly improves relapse-free and overall survival in patients with early-stage and advanced disease. Nonetheless, considerable proportions of patients develop resistance to treatment, highlighting the need for additional and co-adjuvant therapeutic strategies. HER2-specific antibodies can trigger natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity and indirectly enhance the development of tumor-specific T cell immunity; both mechanisms contributing to their antitumor efficacy in preclinical models. Antibody-dependent NK cell activation results in the release of cytotoxic granules as well as the secretion of pro-inflammatory cytokines (i.e., IFNγ and TNFα) and chemokines. Hence, NK cell tumor suppressive functions include direct cytolytic killing of tumor cells as well as the regulation of subsequent antitumor adaptive immunity. Albeit tumors with gene expression signatures associated to the presence of cytotoxic lymphocyte infiltrates benefit from trastuzumab-based treatment, NK cell-related biomarkers of response/resistance to HER2-specific therapeutic antibodies in breast cancer patients remain elusive. Several variables, including (i) the configuration of the patient NK cell repertoire; (ii) tumor molecular features (i.e., estrogen receptor expression); (iii) concomitant therapeutic regimens (i.e., chemotherapeutic agents, tyrosine kinase inhibitors); and (iv) evasion mechanisms developed by progressive breast tumors, have been shown to quantitatively and qualitatively influence antibody-triggered NK cell responses. In this review, we discuss possible interventions for restoring/enhancing the therapeutic activity of HER2 therapeutic antibodies by harnessing NK cell antitumor potential through combinatorial approaches, including immune checkpoint blocking/stimulatory antibodies, cytokines and toll-like receptor agonists.

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“…More specifically, the CD4/CD8 T-cell ratio was significantly increased by the administration of B100 to HTM. We previously described a preferred CD4 T cell activation over an activation of cytotoxic T cells in HTM both without [19] and with antibody (trastuzumab) treatment [20]. Thus, a cytotoxic CD4 cell activity triggered by the application of therapeutic antibodies seems to play a relevant role in HTM.…”

Section: Discussionmentioning

confidence: 98%

“…Tissue specimens (tumor, spleen, liver, brain, and lung) were prepared as previously described [19,20]. Briefly, samples were fixed with 4% formalin and embedded in paraffin.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Mice were generated by transplantation of SK-BR-3 tumor cells with (HTM) or without (TM) the additional transplantation of CD34 + HSC derived from CB. HTM were characterized by tumor cell proliferation in the peritoneum (ascites; peritoneal tumor cells = PTC), by their sensitivity or resistance to trastuzumab treatment, and by the amount of metastases formation in different organs [19,20]. In the age of 9 weeks, treatment with mAb started and was continued for 12 weeks or until animals showed indications of severe sickness.…”

Section: B100 Treatment Eliminates Tumor Cells In a Trastuzumab Resismentioning

confidence: 99%

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A novel rabbit derived anti-HER2 antibody with pronounced therapeutic effectiveness on HER2-positive breast cancer cells in vitro and in humanized tumor mice (HTM)

et al. 2020

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Background: Antibody based cancer therapies have achieved convincing success rates combining enhanced tumor specificity and reduced side effects in patients. Trastuzumab that targets the human epidermal growth factor related receptor 2 (HER2) is one of the greatest success stories in this field. For decades, trastuzumab based treatment regimens are significantly improving the prognosis of HER2-positive breast cancer patients both in the metastatic and the (neo-) adjuvant setting. Nevertheless, ≥ 50% of trastuzumab treated patients experience de-novo or acquired resistance. Therefore, an enhanced anti-HER2 targeting with improved treatment efficiency is still aspired. Methods: Here, we determined cellular and molecular mechanisms involved in the treatment of HER2-positive BC cells with a new rabbit derived HER2 specific chimeric monoclonal antibody called "B100″. We evaluated the B100 treatment efficiency of HER2-positive BC cells with different sensitivity to trastuzumab both in vitro and in the presence of a human immune system in humanized tumor mice. Results: B100 not only efficiently blocks cell proliferation but more importantly induces apoptotic tumor cell death. Detailed in vitro analyses of B100 in comparison to trastuzumab (and pertuzumab) revealed equivalent HER2 internalization and recycling capacity, similar Fc receptor signaling, but different HER2 epitope recognition with high binding and treatment efficiency. In trastuzumab resistant SK-BR-3 based humanized tumor mice the B100 treatment eliminated the primary tumor but even more importantly eradicated metastasized tumor cells in lung, liver, brain, and bone marrow. Conclusion: Overall, B100 demonstrated an enhanced anti-tumor activity both in vitro and in an enhanced preclinical HTM in vivo model compared to trastuzumab or pertuzumab. Thus, the use of B100 is a promising option to complement and to enhance established treatment regimens for HER2-positive (breast) cancer and to overcome trastuzumab resistance. Extended preclinical analyses using appropriate models and clinical investigations are warranted.

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IL-15 enhances the anti-tumor activity of trastuzumab against breast cancer cells but causes fatal side effects in humanized tumor mice (HTM)

Cited by 24 publications

References 48 publications

Immunobiology of the IL-15/IL-15Rα complex as an antitumor and antiviral agent

Immunobiology of the IL-15/IL-15Rα complex as an antitumor and antiviral agent

Interplay between Natural Killer Cells and Anti-HER2 Antibodies: Perspectives for Breast Cancer Immunotherapy

A novel rabbit derived anti-HER2 antibody with pronounced therapeutic effectiveness on HER2-positive breast cancer cells in vitro and in humanized tumor mice (HTM)

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