A phase I study of combined modality fever-range, long-duration, low-temperature whole-body hyperthermia (LL-WBH) optimally-timed with cisplatin (CIS)-gemcitabine (GEM) &amp; interferon-a (IFN-a)

Bull, J. M.; Scott, Gina B.; Nagle, Verne L.; Strebel, F. R.; Koch, Stefan

doi:10.1016/s0959-8049(01)80763-2

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“…Similar reasoning has previously led others to test whether the anti-tumor effect of chemotherapeutic agents (Bull et al, 2001;Sakaguchi et al, 1994;Sumiyoshi et al, 2003;Toyota et al, 1997) can also be enhanced by fever-range whole body hyperthermia (FR-WBH) and this work is being pursued in the clinic, in combination with other cytokines. Here it was shown that thermal pretreatment increased the efficacy of a suboptimal dose (100 ng/mouse/day) of IL-12 to that achieved when a 300 ng/mouse/day was used alone.…”

Section: Discussionmentioning

confidence: 73%

The Anti-Tumor Effect of Interleukin-12 is Enhanced by Mild (Fever-Range) Thermal Therapy

Pritchard

Wolf

Kraybill

et al. 2005

Immunological Investigations

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The cytokine interleukin 12 (IL-12) has resulted in notable anti-tumor activity in animal models and in patients and as a result there is considerable interest in learning how to maximize its therapeutic potential while at the same time reducing its known toxic side effects. Strategies which could maintain its effectiveness while permitting reduced dosage could be especially valuable. In this study we used BALB/c mice bearing CT26 tumors as a model for testing whether combining murine IL-12 with a mild (fever range) whole body hyperthermia protocol could result in such a strategy. Our data revealed that 100 ng of IL-12/mouse/day used in combination with FR-WBH was as effective as one in which 300 ng of IL-12/mouse/day was used alone. Importantly, the mice receiving the combination treatment exhibited fewer treatment related toxicities compared to those that received high dose IL-12 alone. Initiation of the IL-12 treatment immediately after FR-WBH induced the greatest anti-tumor effect. This effect does not appear to depend on differences in IL-12-induced IFN-gamma, but may involve production of nitric oxide (NO), since treatment of mice with a NOS inhibitor, NG-monomethyl-L-arginine (L-NMA), abolishes the additive anti-tumor effect of the combination treatment. Collectively, these data suggest that modification of physiological parameters in the host by mild fever-like thermal stimuli may be an effective and feasible adjuvant for cytokine-based immunotherapeutic strategies.

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Section: Discussionmentioning

confidence: 73%