ZIOP-PGEN Fundamental & Technical Discussion Board - finished the article on localized IL-12 and some comments about blocking NRP-1 in GBM, maybe next st - ZIOP-PGEN Fundamental & Technical Discussion Board - InvestorVillage
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Msg  21297 of 22409  at  11/27/2020 4:00:14 PM  by


finished the article on localized IL-12 and some comments about blocking NRP-1 in GBM, maybe next step?

>> from the conclusion of the IL-12 paper:

IL-12 enhances cytotoxic T and NK cell activity while reversing tumor-induced immunosuppression, inhibiting angiogenesis, increasing lymphocyte trafficking and antigen presentation either directly or through induction of IFNγ (398). Based on these diverse mechanisms as well as its profound antitumor activity in numerous preclinical studies, IL-12 is arguably one of, if not, the most potent antitumor cytokine evaluated to date. Unfortunately, the much-anticipated clinical translation of IL-12-based immunotherapies suffered a tremendous setback in the late 1990s/early 2000s due to severe clinical toxicities associated with systemic IL-12 injections.

Through the development of several clever approaches to localize IL-12 to the tumor microenvironment while limiting systemic exposure, IL-12-based immunotherapies are making a comeback. Several clinical studies evaluating localized IL-12 have been initiated (Table 2) with more on the way. While each delivery strategy has limitations, the approaches reviewed above may retain enough IL-12 in the tumor while eliminating the need for frequent systemic injections. By reducing the potential for IL-12-mediated toxicities associated with systemic injections, localized IL-12 can expand the therapeutic window and finally allow IL-12 to fulfill its considerable potential.

As exemplified by the current immune-oncology clinical trial landscape, combination approaches appear to be most effective for accelerating clinical impact. Several promising preclinical combination approaches with localized IL-12 are likely to be translated in the near future. There is unprecedented interest in finding immunomodulators that can enhance lymphocytic infiltration in order to improve the efficacy of checkpoint inhibitors. Localized IL-12, based on its ability to drive Th1 responses, enhance cytolytic activity, and protect T cells from PD-1/PD-L1 exhaustion and IFNγ-induced apoptosis may be an ideal partner for checkpoint inhibitors.

If safety concerns are assuaged, localized IL-12 could be used in earlier stage cancer patients as a neoadjuvant to resection. For tumors that are inoperable, combining localized IL-12 with ablation may help increase local as well as distant tumor control. With the interesting combination approaches, as well as the uptick in IL-12-based immunotherapies in clinical trials, there is reason to believe that localized IL-12 may play a major role in cancer immunotherapy in the near future.

Localized Interleukin-12 for Cancer Immunotherapy
>>> and i ran across this recent paper about how blocking NRP-1 neuropilin-1 may help stop the transport of the GSC glioblastoma stem cells to new locations that allow the tumor to avoid elimination:


Glioblastoma multiforme (GBM) is a highly proliferative and locally invasive cancer with poor prognosis and a high recurrence rate. Although anti-VEGF (vascular endothelial growth factor) therapy offers short-term benefit to GBM patients, this approach fails as the tumor develops into a more invasive and drug-resistant phenotype and ultimately recurs. Recently, both glioma stemlike cells (GSCs) and brain tumor–initiating cells (BTICs) have been implicated in GBM recurrence and its resistance to therapy. We observed that patient-derived GBM cells expressing shRNAs of VEGF or neuropilin-1 (NRP-1) attenuate cancer stem cell markers, inhibit the tumor-initiating cell’s neurosphere-forming capacity, and migration. Furthermore, both VEGF and NRP-1 knockdown inhibit the growth of patient-derived GBM xenografts in both zebrafish and mouse models. Interestingly, NRP-1–depleted patient-derived GBM xenografts substantially prolonged survival in mice compared to that of VEGF depletion. Our results also demonstrate that NRP-1 ablation of patient-derived GBM cells improves the sensitivity of TMZ and enhances the overall survival of the respective tumor-bearing mice. This improved outcome may provide insight into the inhibition of GBM progression and effective treatment strategies by targeting NRP-1 in addition to chemotherapy and radiotherapy.

 >>> and here are some references that review aspects of how NRP-1 functions, and involvement in glioblastoma:
>>and this article:
 By applying an unbiased screening approach using a cDNA mammalian expression library generated from human monocyte-derived dendritic cells and probed with recombinant human C4d, we identified neuropilin-1 (NRP1) as a novel receptor for C4d, C3d, and iC3b. NRP1, a highly conserved type 1 transmembrane protein, plays important roles in the development of the nervous and cardiovascular system as well as in tumorigenesis through interaction with its established binding partners, such as vascular endothelial growth factor (VEGF) and semaphorin 3A (Sema3A). NRP1 is also expressed on immune cells and serves as a marker for murine Tregs.

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