Decreased response rates by the combination of histamine and IL-2 in melphalan-based isolated limb perfusion

Abstract

Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting.

Isolated Limb Perfusion with Melphalan and TNF-α in the Treatment of Extremity Sarcoma

“…Also because of the success of IL-2 in ILP and the earlier-mentioned success of Hi in ILP model, we studied if the two drugs combined with melphalan could further improve response rates in an experimental ILP. In a sarcoma-bearing rat ILP model the effects were assessed [ 68 ]. A negative synergistic effect was found between IL-2 and Hi in a regional setting.…”

Future directions in regional treatment strategies for melanoma and sarcoma

“…Similarly, HILP with IL-2 plus melphalan resulted in an OR of 67% compared to an OR of 17% with melphalan alone in the same experimental model [44]. The combination of histamine and IL-2 to melphalan HILP had no further benefit and was found to have an OR of 28%, less than each achieved alone when combined with melphalan HILP [45]. As new agents and modifications to treatment with regional chemotherapy are studied for their potential to improve response, the emphasis on maintaining acceptable treatment associated toxicity should be maintained.…”

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

“…Ongoing research is studying the combined use of immune checkpoint blockade with other immune modulators, surgery, or radiation 288 . In a rat experimental model bearing BN‐175 tumors the association of histamine and IL‐2 in the melphalan‐based isolated limb perfusion setting showed no improved response (40 µg melphalan, 1 mg histamine, and 50 µg IL‐2 in 5 ml total volume perfusate) 289 …”