Evaluation of Recombinant Human Interleukin-12 in Patients with Recurrent or Refractory Ovarian Cancer: A Gynecologic Oncology Group Study

Hurteau, Jean; Blessing, John A.; DeCesare, Steven; Creasman, William T.

doi:10.1006/gyno.2001.6255

Cited by 85 publications

(55 citation statements)

References 17 publications

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“…13 At the clinical level, a Phase I study of the natural sterol squalamine, 32 and Phase II studies of the T cell-and NK cell-regulating factor IL-12, 33 carboxyamidotriazole (a factor inhibiting transmembrane calcium influx in vascular endothelial cells) 34 and thalidomide (known as a phocomeliacausing drug and having powerful antiangiogenic activity) 35 have been reported. It has been confirmed that these molecular-targeting agents have tumor growth-suppressive activity and antiangiogenic activity in subcutaneous tumor models.…”

Section: Discussionmentioning

confidence: 99%

“…13 Tolerability to the 4 drugs at the Phase I and II clinical trial stages has been confirmed. [32][33][34][35] Single-agent IL-12 has a low response rate in recurrent ovarian cancer patients, 33 however, and single-agent carboxyamidotriazole has no tumor-regression activity, only suppressing tumor progression. 34 Because moleculartargeting therapy alone is limited to the tumor-regression effect, it is clinically used in combination with conventional anticancer drugs.…”

Section: Discussionmentioning

confidence: 99%

“…There have been few reports on severe side effects of angiogenesis inhibitors, unlike conventional anticancer drugs, because of their functional specificity. 19,[33][34][35]41,42 It is speculated that because angiogenesis inhibitors target normal cells such as vascular endothelial cells, but not cancer cells themselves, induction of resistance to them does not develop easily. 43 Therefore, as a therapeutic strategy using angiogenesis inhibitors such as SU6668 for ovarian cancer, long-term administration aimed at the prevention of recurrence after remission induction therapy may be useful.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU‐68)

Machida

Saga

Takei

et al. 2004

Intl Journal of Cancer

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SU6668 (TSU-68) is a small-molecule synthetic inhibitor of the angiogenic related receptor tyrosine kinases Flk-1/KDR, PDGFR␤, and FGFR1. Using a mouse model of peritoneally disseminated ovarian cancer, we investigated whether SU6668 inhibits peritoneal dissemination and prolongs survival time. BALB/c nude mice were intraperitoneally (i.p.) inoculated with SHIN-3 (VEGF-hypersecretory) or KOC-2S (PDGF-hypersecretory) ovarian serous adenocarcinoma cells with marked peritoneal dissemination ability. From the day after i.p. inoculation of tumor cells, SU6668 was orally administered 6 times weekly at a daily dose of 100 mg/kg or 400 mg/kg. The SU6668-administered group and the vehicle-administered control group were compared for the number of tumor vascular endothelial cells, weight of peritoneally disseminated tumors, amount of ascitic fluid and survival time. As a result, these 3 parameters were significantly smaller in the SHIN-3-inoculated, SU6668-administered mice than in the control group (p ‫؍‬ 0.03, p ‫؍‬ 0.002, and p ‫؍‬ 0.02, respectively). The mean survival time was significantly longer, at 58.1 ؎ 11.2 days, in the SU6668-administered mice than that (34.5 ؎ 8.8 days) in the control group (p ‫؍‬ 0.002). Similarly, in the KOC-2S-inoculated mice, the oral administration of SU6668 significantly reduced these 3 parameters (p ‫؍‬ 0.04, p ‫؍‬ 0.04, and p ‫؍‬ 0.03, respectively), and significantly prolonged survival (16.6 ؎ 1.7 days vs. 11.0 ؎ 0.7 days, p ‫؍‬ 0.008). Thus, the oral administration of SU6668 inhibited angiogenesis and peritoneal dissemination and prolonged survival in mice with peritoneally disseminated ovarian cancer. These effects were observed with both the VEGF-and PDGF-hypersecretory cell lines. Our results suggest that molecular targeting with oral SU6668 will become a new therapeutic strategy targeting peritoneally disseminated ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU‐68)

Machida

Saga

Takei

et al. 2004

Intl Journal of Cancer

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“…or s.c. injected IL-12 in patients with metastatic renal carcinoma, melanoma, colon carcinoma, recurrent ovarian cancer, and neck and head carcinoma. [111][112][113][114][115][116][117][118] The goal was to administer IL-12 in a schedule that minimized common toxicities associated with cytokine therapy such as fever, fatigue, hematological changes or hyperglycemia. In general, the best way to administer IL-12 appeared to be in cycles consisting of either i.v.…”

Section: Il-12 To Treat Human Cancermentioning

confidence: 99%

“…Even though these trials established maximum tolerated doses for IL-12 for the different schedules, treatment response rates were not very promising, with only few cases of partial or complete responses (Table 1). 111,[113][114][115]118 Moreover, the systemic administration of IL-12 displayed schedule-dependent toxicity, which appeared to be reduced when a single test dose of IL-12 was administered i.v. 2 weeks before initiation of the scheduled daily treatment cycle.…”

Section: Il-12 To Treat Human Cancermentioning

confidence: 99%

New insights into IL-12-mediated tumor suppression

et al. 2014

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During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

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Tumor‐Tailored Ionizable Lipid Nanoparticles Facilitate IL‐12 Circular RNA Delivery for Enhanced Lung Cancer Immunotherapy

Xu,

Solek

et al. 2024

Advanced Materials

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The advancement of mRNA‐based immunotherapies for cancer is highly dependent on the effective delivery of RNA payloads using ionizable lipid nanoparticles (LNPs). However, the clinical application of these therapies is hindered by variable mRNA expression among different cancer types and the risk of systemic toxicity. The transient expression profile of mRNA further complicates this issue, necessitating frequent dosing and thus increasing the potential for adverse effects. Addressing these challenges, we utilized a high‐throughput combinatorial method to synthesize and screen LNPs that efficiently deliver circular RNA (circRNA) to lung tumors. Our lead LNP, H1L1A1B3, demonstrated a fourfold increase in circRNA transfection efficiency in lung cancer cells over ALC‐0315, the industry‐standard LNPs, while providing potent immune activation. A single intratumoral injection of H1L1A1B3 LNPs, loaded with circRNA encoding interleukin‐12 (IL‐12), induced a robust immune response in a Lewis lung carcinoma model, leading to marked tumor regression. Immunological profiling of treated tumors revealed substantial increments in CD45+ leukocytes and enhanced infiltration of CD8+ T cells, underscoring the ability of H1L1A1B3 LNPs to modulate the tumor microenvironment favorably. These results highlight the potential of tailored LNP platforms to advance RNA drug delivery for cancer therapy, broadening the prospects for RNA immunotherapeutics.This article is protected by copyright. All rights reserved

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Evaluation of Recombinant Human Interleukin-12 in Patients with Recurrent or Refractory Ovarian Cancer: A Gynecologic Oncology Group Study

Cited by 85 publications

References 17 publications

Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU‐68)

Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU‐68)

New insights into IL-12-mediated tumor suppression

Tumor‐Tailored Ionizable Lipid Nanoparticles Facilitate IL‐12 Circular RNA Delivery for Enhanced Lung Cancer Immunotherapy

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