Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival

Alkins, Ryan; Burgess, Alison; Kerbel, Robert S.; Wels, Winfried S.; Hynynen, Kullervo

doi:10.1093/neuonc/nov318

Cited by 108 publications

(84 citation statements)

References 28 publications

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“…Interestingly, in our study as well as studies by Park (Park et al 2012) an Alkins (Alkins et al 2016) a response was observed only in some of the animals. Both studies used tumor model based on HER2-positive cells from a breast cancer patient.…”

Section: Discussionsupporting

confidence: 63%

Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption

Kobus

Zervantonakis

Zhang

et al. 2016

Journal of Controlled Release

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HER2-targeting antibodies (i.e. trastuzumab and pertuzumab) prolong survival in HER2-positive breast cancer patients with extracranial metastases. However, the response of brain metastases to these drugs is poor, and it is hypothesized that the blood-brain barrier (BBB) limits drug delivery to the brain. We investigated whether we could improve the response by temporary disruption of the BBB using focused ultrasound in combination with microbubbles. To study this, we inoculated 30 nude rats with HER2-positive cells derived from a brain metastasis of a breast cancer patient (MDA-MB-361). The animals were divided into three groups: a control-group that received no treatment; an antibody-only group that received six weekly treatments of trastuzumab and pertuzumab; and an ultrasound+antibody group that received trastuzumab and pertuzumab in combination with six weekly sessions of BBB disruption using focused ultrasound. In two animals, the leakiness of the tumors before disruption was evaluated using contrast-enhanced T1-weighted magnetic resonance imaging and found that the tumors were not leaky. The same technique was used to evaluate the effectiveness of BBB disruption, which was successful in all sessions. The tumor in the control animals grew exponentially with a growth constant of 0.042±0.011 mm3/day. None of the antibody-only animals responded to the treatment and the growth constant was 0.033±0.009 mm3/day during the treatment period. Four of the ten animals in the ultrasound+antibody-group showed a response to the treatment with an average growth constant of 0.010±0.007 mm3/day, compared to a growth constant 0.043±0.013 mm3/day for the six non-responders. After the treatment period, the tumors in all groups grew at similar rates. As the tumors were not leaky before BBB disruption and there were no responders in the antibody-only group, these results show that at least in some cases disruption of the BBB is necessary for a response to the antibodies in these brain metastases. Interestingly, only some of the rats responded to the treatment. We did not observe a difference in tumor volume at the start of the treatment, nor in HER2 expression or in contrast-enhancement on MRI between the responders and non-responders to explain this. Better understanding of why certain animals respond is needed and will help in translating this technique to the clinic. In conclusion, we demonstrate that BBB disruption using focused ultrasound in combination with antibody therapy can inhibit growth of breast cancer brain metastasis.

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Section: Discussionsupporting

confidence: 63%

Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption

Kobus

Zervantonakis

Zhang

et al. 2016

Journal of Controlled Release

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“…27 These cells have been studied both preclinically, and now clinically as a stand-alone anticancer therapeutic. 28,29 In addition, these cells do not display CD5 on their surface, which allows for expression of the CD5-VLR-CAR without self-activation and killing of transduced cells. Given the poor transduction efficiency of NK-92 cells (<10%), a construct incorporating a GFP P2A sequence was created (Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

Genetic engineering of chimeric antigen receptors using lamprey derived variable lymphocyte receptors

Moot

Raikar

Fleischer

et al. 2016

Molecular Therapy - Oncolytics

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Chimeric antigen receptors (CARs) are used to redirect effector cell specificity to selected cell surface antigens. Using CARs, antitumor activity can be initiated in patients with no prior tumor specific immunity. Although CARs have shown promising clinical results, the technology remains limited by the availability of specific cognate cell target antigens. To increase the repertoire of targetable tumor cell antigens we utilized the immune system of the sea lamprey to generate directed variable lymphocyte receptors (VLRs). VLRs serve as membrane bound and soluble immune effectors analogous but not homologous to immunoglobulins. They have a fundamentally different structure than immunoglobulin (Ig)-based antibodies while still demonstrating high degrees of specificity and affinity. To test the functionality of VLRs as the antigen recognition domain of CARs, two VLR-CARs were created. One contained a VLR specific for a murine B cell leukemia and the other contained a VLR specific for the human T cell surface antigen, CD5. The CAR design consisted of the VLR sequence, myc-epitope tag, CD28 transmembrane domain, and intracellular CD3ζ signaling domain. We demonstrate proof of concept, including gene transfer, biosynthesis, cell surface localization, and effector cell activation for multiple VLR-CAR designs. Therefore, VLRs provide an alternative means of CAR-based cancer recognition.

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“…So far, the following statements can be made: the ARF pushes microbubbles toward the vascular wall and promotes an impact on vascular cells that induces a loose intercellular gap; and microbubbles inside the vasculature can produce microstreams and shock waves, thus compromising the stability of the vascular wall. After the safe BBB disruption with focused ultrasound (FUS) and microbubbles (Figure 6), NK-92 cells are largely delivered into brain tumor tissues and exert their anticancer effects, causing a higher suppression of tumor growth and longer survival time in a mouse brain tumor model compared to the non-treatment prototype 81. Alkins et al labeled HER2 high-expressing breast tumor cells with superparamagnetic iron oxide (SPIO) and implanted them into nude rats.…”

Section: Immunotherapy Assisted By Ummdmentioning

confidence: 99%

Ultrasound-mediated microbubble destruction: a new method in cancer immunotherapy

Zhang

Jia

et al. 2018

OTT

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Immunotherapy provides a new treatment option for cancer. However, it may be therapeutically insufficient if only using the self-immune system alone to attack the tumor without any aiding methods. To overcome this drawback and improve the efficiency of therapy, new treatment methods are emerging. In recent years, ultrasound-mediated microbubble destruction (UMMD) has shown great potential in cancer immunotherapy. Using the combination of ultrasound and targeted microbubbles, molecules such as antigens or genes encoding antigens can be efficiently and specifically delivered into the tumor tissue. This review focuses on the recent progress in the application of UMMD in cancer immunotherapy.

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Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival

Abstract: Many tumor proteins could be exploited for targeted therapy with the NK-92 cell line; combined with the mounting safety evidence for transcranial ultrasound, these results may soon be translatable to a highly targeted treatment option for patients with brain tumors.

Cited by 108 publications

References 28 publications

Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption

Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption

Genetic engineering of chimeric antigen receptors using lamprey derived variable lymphocyte receptors

Ultrasound-mediated microbubble destruction: a new method in cancer immunotherapy

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