Splenic artery infusion of IL-2 might allow treatment of melanoma and renal cell cancer with less side effects and greater efficacy

Abstract

EditorialIntravenous administration of interleukin-2 (IL-2) is a useful therapy for stage IV melanoma and renal cell cancer, stimulating proliferation of T cells, lymphocyte activated killer cells, natural killer cells and other immune effectors, which then target and eliminate cancer cells. In about 15 % of patients, tumor burden is significantly lessened and complete cure is seen in 6 -8 %. 1-3 However, IL-2 therapy can cause severe side effects including pulmonary edema, psychosis, renal failure, hepatitis and myocardial infarctions. 3 The treatment protocols basically simulate septic shock to get an immune response against cancer. Patients have to pass a cardiac stress test before starting IL-2, and as a result many patients are precluded from even starting IL-2 therapy. Those medically cleared for the grueling protocol undergo intensive care level monitoring while receiving IL-2 infusions. Even for patients able to tolerate IL-2 therapy without permanent harm, almost always the number of doses given in any cycle is well below the optimal amount because of patients start showing unacceptable side effects. I personally have had the experience of patients experiencing severe shaking rigors, at the very threshold of threatened end organ damage, yet desperately pleading for just one more dose of IL-2, to get just that much more chance of disease-free survival. Those desperate patients prompt me to propose to this audience that we should consider reviving the old idea of administering IL-2 into the splenic artery instead of the systemic circulation.The concept of splenic artery infusion of IL-2 for cancer immunotherapy goes back over a quarter of a century, but new efforts are needed. The basic premise, validated in data so far, is that you need far smaller amounts of intrasplenically infused IL-2 to get maximum immune response, and most, if not all, of the IL-2 has its action within the spleen rather than the systemic circulation. The spleen gives rise to 25 % of total circulating T lymphocytes and 10 -15 % of B lymphocytes, and about 50 % of all lymphocytes in the body are thought to pass through the splenic arterioles in the course of their lifetime. The spleen receives 100 % of its arterial blood supply from the splenic artery, making percutaneous access relatively easy. Pilot testing of splenic artery infusion of IL-2 first took place in mouse models in the mid 1980's. 4 Subsequently in 1990, 20 patients with stage IV renal cell cancer, melanoma and lymphoma underwent a phase I clinical trial with low dose IL-2 continuously infused over 5 consecutive days at 3 weeks intervals for 2 -4 cycles via a splenic arterial catheter placed through the femoral artery. 5 Each patient received from 90,000 -240,000 IU/kg/day for a total dose of 450,000-1.2 millionIU/kg/cycle, much lower than the maximum dose of 8.4 million IU/kg/cycle with current systemic IL-2. In 3 of the 20 patients, visible reduction of tumor burden could be demonstrated. Two patients with renal cell cancer had complete regression of hepatic metastase...