Low-Dose Cyclophosphamide and Continuous-Infusion Interleukin-2 with Famotidine in Previously Treated Metastatic Melanoma or Kidney Cancer

Quan, Walter; Quan, Francine M.; King, Linda A.; Walker, Paul R.

doi:10.1089/cbr.2007.0420

Cited by 5 publications

(1 citation statement)

References 27 publications

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“…Sensitization may occur as a result of reducing intra-tumoral pressure and lowering the macromolecular diffusion barrier, thus potentially permitting increased uptake of the immunocytokine antibodies. Moreover, existing clinical evidence suggests the combination of low-dose cyclophosphamide together with a continuous-infusion or IL2 or other related biologics yields significant anti-tumor activity in patients with advanced cancers [23,24]. These effects have been shown to be related to differential loss of regulatory T-cells compared with cytotoxic lymphocyte populations.…”

Section: Discussionmentioning

confidence: 99%

A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors

Cristea

Lewis

et al. 2013

BMC Cancer

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BackgroundHumanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent.MethodsPhase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on day 1), and escalating doses of huKS-IL2 (0.5–4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated.ResultsTwenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m2 cyclophosphamide was 3.0 mg/m2. At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade 3/4 adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for ≥ 4 cycles in 3 patients.ConclusionThe combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients showed stable disease for ≥ 4 cycles.Trial registrationhttp://NCT00132522

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Section: Discussionmentioning

confidence: 99%

A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors

Cristea

Lewis

et al. 2013

BMC Cancer

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Histamine in cancer immunology and immunotherapy. Current status and new perspectives

Sarasola

Delgado

Nicoud

et al. 2021

Pharmacology Res & Perspec

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Cancer is the second leading cause of death globally and its incidence and mortality are rapidly increasing worldwide. The dynamic interaction of immune cells and tumor cells determines the clinical outcome of cancer. Immunotherapy comes to the forefront of cancer treatments, resulting in impressive and durable responses but only in a fraction of patients. Thus, understanding the characteristics and profiles of immune cells in the tumor microenvironment (TME) is a necessary step to move forward in the design of new immunomodulatory strategies that can boost the immune system to fight cancer. Histamine produces a complex and fine‐tuned regulation of the phenotype and functions of the different immune cells, participating in multiple regulatory responses of the innate and adaptive immunity. Considering the important actions of histamine‐producing immune cells in the TME, in this review we first address the most important immunomodulatory roles of histamine and histamine receptors in the context of cancer development and progression. In addition, this review highlights the current progress and foundational developments in the field of cancer immunotherapy in combination with histamine and pharmacological compounds targeting histamine receptors.

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Cyclophosphamide Promotes Chronic Inflammation–Dependent Immunosuppression and Prevents Antitumor Response in Melanoma

Sevko

Sade-Feldman²,

Kanterman³

et al. 2013

Journal of Investigative Dermatology

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Low-dose cyclophosphamide (CP) therapy induces immunogenic tumor cell death and decreases regulatory T cell (Treg) numbers in mice with transplantable tumors. Using the ret transgenic murine melanoma model that resembles human melanoma, we detected no beneficial antitumor effects with such treatment, despite a decrease in Tregs. On the contrary, low-dose CP enhanced the production of chronic inflammatory mediators in melanoma lesions associated with increased accumulation of Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs), which exhibit elevated suppressive activity and nitric oxide (NO) production as well as inhibition of T-cell proliferation. Moreover, the frequencies of CD8(+) T cells in the tumors and their ability to produce perforin were decreased. To study whether the observed CP-induced MDSC expansion and activation also occurs under chronic inflammatory tumor-free conditions, mice exhibiting chronic inflammation were treated with CP. Similar to tumor-bearing mice, CP-treated inflamed mice displayed elevated levels of MDSCs with enhanced production of NO, reactive oxygen species, and a suppressed in vivo natural killer (NK) cell cytotoxic activity indicating CP effects on the host immune system independent of the tumor. We suggest that melanoma therapy with low-dose CP could be efficient only when combined with the neutralization of MDSC immunosuppressive function and chronic inflammatory microenvironment.

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Low-Dose Cyclophosphamide and Continuous-Infusion Interleukin-2 with Famotidine in Previously Treated Metastatic Melanoma or Kidney Cancer

Cited by 5 publications

References 27 publications

A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors

A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors

Histamine in cancer immunology and immunotherapy. Current status and new perspectives

Cyclophosphamide Promotes Chronic Inflammation–Dependent Immunosuppression and Prevents Antitumor Response in Melanoma

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