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Old 10-22-2018, 02:55 PM   #1
Lani
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Lightbulb incredible futuristic treatment of her2+ brain mets being developed!!

J Control Release. 2018 Oct 17. pii: S0168-3659(18)30588-1. doi: 10.1016/j.jconrel.2018.10.017. [Epub ahead of print]
Successful intracranial delivery of trastuzumab by gene-therapy for treatment of HER2-positive breast cancer brain metastases.
Zafir-Lavie I1, Sherbo S2, Goltsman H2, Badinter F2, Yieni E3, Ofek P3, Miari R2, Tal O2, Liran A2, Shatil T2, Krispel S2, Shapir N2, Neil GA4, Benhar I5, Panet A6, Fainaro RS3.
Author information
1
Medgenics Medical Israel, Ltd., Misgav, Israel; Aevi Genomic Medicine, Inc., Wayne, PA, USA. Electronic address: Inbal.ZafirLavie@gmail.com.
2
Medgenics Medical Israel, Ltd., Misgav, Israel.
3
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Room 607, Tel Aviv University, Tel-Aviv 69978, Israel.
4
Aevi Genomic Medicine, Inc., Wayne, PA, USA.
5
School of Molecular Cell Biology and Biotechnology, Green Building, Room 202, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel.
6
Department of Biochemistry (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Abstract
BACKGROUND:
Trastuzumab is a monoclonal antibody which demonstrates efficacy for HER2 positive breast cancer patients. Recently, an increased incidence of brain metastasis in trastuzumab-treated patients has been reported. The reason for this may be the effectiveness of systemic trastuzumab allowing patients to survive longer thus providing time for brain metastases to develop, along with the lack of penetration of systemic therapies through the blood brain barrier. In recent years, several administration routes to the brain have been evaluated. Albeit advances in the field, there is still a need for improved delivery of therapeutic antibodies to the brain. To address this challenge, we have developed two gene therapy-based methods enabling continuous secretion of active trastuzumab in the brain.

METHODS:
We have developed two gene therapy approaches for the delivery of the therapeutic anti-HER2 monoclonal antibody, trastuzumab, to the brain. We utilized the helper dependent adenovirus vector, containing trastuzumab light and heavy chains coding sequences (HDAd-trastuzumab). in the first approach, we used the Transduced Autologous Restorative Gene Therapy (TARGT) platform, in which dermal fibroblasts of human and mouse origin, are ex-vivo transduced with HDAd-trastuzumab vector, rendering continuous secretion of active trastuzumab from the cells locally. These genetically engineered cells were subsequently implanted intracranially to mice, contralateral to HER2 positive breast carcinoma cells inoculation site, enabling continuous secretion of trastuzumab in the brain. In the second approach, we used the same HDAd-trastuzumab viral vector, directly injected intracranially, contralateral to the HER2 positive breast carcinoma cells inoculation site. Both methods enabled therapeutic concentrations of local in-vivo production of active trastuzumab in a mouse model of brain metastatic breast cancer.

RESULTS:
Trastuzumab secreted from the TARGT platform demonstrated in-vitro affinity and immune recruitment activity (ADCC) similar to recombinant trastuzumab (Herceptin, Genentech). When implanted in the brain of HER2 positive tumor-bearing mice, both the TARGT platform of dermal fibroblasts engineered to secrete trastuzumab and direct injection of HDAd-trastuzumab demonstrated remarkable intracranial tumor growth inhibitory effect.

CONCLUSIONS:
This work presents two gene therapy approaches for the administration of therapeutic antibodies to the brain. The TARGT platform of dermal fibroblasts engineered to secrete active trastuzumab, and the direct injection of HDAd-trastuzumab viral vector, both rendered continuous in-vivo secretion of active trastuzumab in the brain and demonstrated high efficacy. These two approaches present a proof of concept for promising gene therapy based administration methods for intracranial tumors as well as other brain diseases.

Copyright 2018. Published by Elsevier B.V.

KEYWORDS:
Brain drug-delivery; Brain-metastasis; Gene-therapy; HER2; Immunotherapy; Viral-vector
PMID: 30342077 DOI: 10.1016/j.jconrel.2018.10.017
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Old 10-23-2018, 12:00 AM   #2
Pamelamary
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Re: incredible futuristic treatment of her2+ brain mets being developed!!

Sounds exciting, Lani , but I do get a bit depressed at times at the gap between research like this and its implementation. Too many women I know have died recently.....
Best wishes... Pam
__________________
Diagnosed 2004: Lumpectomy - 2 tumours, both grade 1 infiltrating duct carcinoma, about 12mm. ER+,
C-erbB-2 status 3+.
Clear margins, no nodal involvement.
Radiotherapy, i year Tamoxifen, 4 years Arimidex.
Rediagnosed 2012: Multiple bone metastases.
3/12: began on Marianne trial - T-DM1 + Pertuzamab/Placebo.
5/12:Unexpected development of numerous bilateral liver mets. Came off trial.
Started Docetaxol/ Herceptin + Zometa.
8/12:Bones stable +major regression in liver (!)
9/12:Can't take any more Docetaxol! Start on Herceptin and Tamoxifen. Cross fingers!
Changed to Denosumab.
11/12: Scan shows stable - yay!
11/13: Still stable :-) !!!
1/16: All stable, but lowered calcium, so switched to Zometa 3 monthly.
2/19: Happily still stable on Herceptin, Letrozole and 3 monthly Zometa.
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Old 12-08-2018, 06:35 AM   #3
lkc Gumby
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Re: incredible futuristic treatment of her2+ brain mets being developed!!

Indeed, exciting news. Hopefully US investigators will jump on this soon!
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Linda

Dxed Stage IIIC May 05, 12 pos nodes
er/pr -neg,Her -pos
LVI
Right partial mast & partial axillary dissection-June14,2005
Right modified mast-no clear margins- June 30, 2005
DD AC x4
Taxotere X4 with Herceptin
Rads x 35( 5 fields )
Left prophylactive mast( atypia & hyperplasia found ),
put on Tamoxifen x 1 yr; D/ced due to endometrial thickening
bilateral recon (saline implants)May 06
Nipple recon July 06
metformin 2010
removal of implants due to severe encapsulation, insertion of gummies 2013
Reclast Q yr
NED!!!
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