Prospects for combining targeted and conventional cancer therapy with immunotherapy

Gotwals, Philip J.; Cameron, Scott; Cipolletta, Daniela; Cremasco, Viviana; Crystal, Adam S.; Hewes, Becker; Mueller, Brett H.; Quaratino, Sonia; Sabatos-Peyton, Catherine; Petruzzelli, Lilli; Engelman, Jeffrey A.; Dranoff, Glenn

doi:10.1038/nrc.2017.17

Cited by 823 publications

(592 citation statements)

References 182 publications

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“…3). These data support a model where careful scheduling/dosing of mTOR inhibitors can directly benefit anti-tumour immune-checkpoint therapy, 52,53 and provide a clear rationale for exploration of vistusertib/immune checkpoint blockade in the clinic. It is of note that vistusertib treatment resulted in a bell-shaped phenotypic response in T-cells, with the maximal potentiating effect observed at around the IC 50 for pathway inhibition.…”

Section: Discussionsupporting

confidence: 55%

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

et al. 2018

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ABSTRACTmTOR inhibition can promote or inhibit immune responses in a context dependent manner, but whether this will represent a net benefit or be contraindicated in the context of immunooncology therapies is less understood. Here, we report that the mTORC1/2 dual kinase inhibitor vistusertib (AZD2014) potentiates anti-tumour immunity in combination with anti-CTLA-4 (αCTLA-4), αPD-1 or αPD-L1 immune checkpoint blockade. Combination of vistusertib and immune checkpoint blocking antibodies led to tumour growth inhibition and improved survival of MC-38 or CT-26 pre-clinical syngeneic tumour models, whereas monotherapies were less effective. Underlying these combinatorial effects, vistusertib/immune checkpoint combinations reduced the occurrence of exhausted phenotype tumour infiltrating lymphocytes (TILs), whilst increasing frequencies of activated Th1 polarized T-cells in tumours. Vistusertib alone was shown to promote a Th1 polarizing proinflammatory cytokine profile by innate primary immune cells. Moreover, vistusertib directly enhanced activation of effector T-cell and survival, an effect that was critically dependent on inhibitor dose. Therefore, these data highlight direct, tumour-relevant immune potentiating benefits of mTOR inhibition that complement immune checkpoint blockade. Together, these data provide a clear rationale to investigate such combinations in the clinic.

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Section: Discussionsupporting

confidence: 55%

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

et al. 2018

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“…The phase 3 trial ONO-4538-12 (ATTRACTION-2) revealed the efficacy and safety of programmed cell death protein 1 (PD-1) blockade by monoclonal antibody nivolumab in Asian patients with esophagogastric (n = 30) and gastric adenocarcinoma (n = 272) [2]. Currently, in terms of a predictor of response to immune checkpoint inhibitor, much focus is being placed on the microsatellite instability (MSI) status [3]. However, little is known about the MSI status in EGJ adenocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

Recent Incidence Trend of Surgically Resected Esophagogastric Junction Adenocarcinoma and Microsatellite Instability Status in Japanese Patients

et al. 2018

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Background: The incidence trend of esophagogastric junction (EGJ) adenocarcinoma in Japan has not been sufficiently investigated. Little is known about the microsatellite instability (MSI) status of this tumor. Summary: Previously published studies analyzing the trend of EGJ adenocarcinoma in Japan were reviewed. And a trend of surgically resected cases (Siewert type I-III) utilizing a retrospective multicenter cohort of 379 patients from 4 academic institutions in Japan investigated. Although an increasing trend in the last 2 reports was considered controversial, our cohort demonstrated a growing number of EGJ adenocarcinoma cases between 2006 and 2013. This trend was evident, especially in Siewert type I cases. In the previous 16 studies that performed MSI testing, MSI-high tumors ranged 0–8.3%, though there were no fixed microsatellite markers on EGJ adenocarcinoma. In a recent comprehensive genetic analysis by The Cancer Genome Atlas, MSI testing using the following 7 markers, BAT25, BAT26, BAT40, D2S123, D5S346, D17S250 and TGFR-II showed a favorable correlation with hypermutated tumors. We performed MSI testing using 6 of those markers, except TGFR-II, on 206 cases from one institution, and detected 15 cases (7.3%) with MSI-high. The prevalence of MSI-high was 0% in Siewert type I, 7.6% in type II, and 16.7% in type III. Key message: The number of surgically resected EGJ adenocarcinoma cases gradually increased, and MSI-high was infrequent in Siewert type I-II tumors in our Japanese cohort. Considering MSI-high as a predictive biomarker for emerging immune checkpoint inhibitors, MSI status is becoming more beneficial in EGJ adenocarcinoma.

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“…[1][2][3] Since the first Food and Drug Administration (FDA)-approved TMA in 1986, the market of TMAs has grown exponentially, with approximately 50 antibodies approved and over 70 expected in 2020. 4 Among them, TMAs targeting the tyrosine kinase receptors that are overexpressed in several tumor cell subsets (eg, trastuzumab [TZ; Trastuzumab-Herceptinhave initiated a new paradigm for targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

Colzani¹,

Pandolfi²,

Hoti³

et al. 2018

IJN

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Background We report the development of an efficient antibody delivery system for the incorporation of trastuzumab (TZ) into poly(lactic- co -glycolic) acid nanoparticles (PLGA NPs). The aim of the work was to overcome the current limitations in the clinical use of therapeutic antibodies, including immunogenicity, poor pharmacokinetics, low tumor penetration and safety issues. Materials and methods Trastuzumab-loaded PLGA NPs (PLGA-TZ) were synthesized according to a double emulsion method. The same protocol was used to produce control batches of nonspecific IgG-loaded NPs and empty PLGA NPs. After release of TZ from PLGA NPs, the effects on the main biological activities of the antibody were evaluated on SKBR3 (human epidermal growth factor receptor 2 [HER2]-positive breast cancer cell line), including specific binding to HER2, phosphorylation of HER2 (Y1248), degradation of HER2 protein and antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. In addition, an MTT assay was performed for treating SKBR3 cells with PLGA NPs loaded with TZ and doxorubicin to evaluate the cytotoxic activity of the combined treatment. Results and discussion TZ was gradually released in a prolonged way over 30 days. The physical characterization performed with circular dichroism, Fourier transform infrared and fluorescence spectroscopy of TZ after release demonstrated that no structural alterations occurred compared to the native antibody. In vitro experiments using SKBR3 cells showed that TZ released from PLGA NPs maintained the same biological activity of native TZ. PLGA NPs allowed a good co-encapsulation efficiency of TZ and doxorubicin resulting in improved therapy. Conclusion With the TZ case study, we demonstrate that the distinctive features of therapeutic monoclonal antibodies, including molecular targeting efficiency, capability to inhibit or properly affect the regulatory signaling pathways of cancer cells and stimulation of the ADCC, are fully preserved after loading into and release from PLGA NPs. In addition, PLGA NPs are shown to allow for the simultaneous incorporation of TZ and conventional chemotherapeutics, resulting in a potent antitumor nanodrug well suited for in situ combination and neoadjuvant therapy.

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Prospects for combining targeted and conventional cancer therapy with immunotherapy

Cited by 823 publications

References 182 publications

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

Combination of dual mTORC1/2 inhibition and immune-checkpoint blockade potentiates anti-tumour immunity

Recent Incidence Trend of Surgically Resected Esophagogastric Junction Adenocarcinoma and Microsatellite Instability Status in Japanese Patients

Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles

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