Phase II study of interleukin-12 for treatment of plateau phase multiple myeloma (E1A96): A trial of the Eastern Cooperative Oncology Group

Abstract

The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of interleukin-12 (IL-12) for plateau phase multiple myeloma. Patients were initially treated with IL-12 250 ng/kg I.V. daily for 5 days every 3 weeks. The trial was modified due to toxicity after the first 16 patients. IL-12 was given 300 ng/kg subcutaneously twice weekly for 24 weeks. Of 48 eligible patients, there were 4 objective responses (8.3%), all CR. The median survival and progression-free survival were 42.8 and 11.4 months. Unacceptable grade 3 or 4 non-hematologic toxicity (31% with IL-12 subcutaneously and 63% with IL-12 intravenously) was observed.

Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors

“…synNotch controlled production of IL-10 or other suppressive cytokines could be used to locally suppress inflammation in autoimmune or inflammatory disease (O'Garra et al, 2008). Locally concentrated IL-12 production, or that of other immune stimulatory factors, in tumors could drive potent innate immune responses to cancer while reducing the chances of highly toxic effects that have been observed with systemic administration of IL-12 (Lacy et al, 2009). Combined cytokine and chemokine programs such as the local production of IL-2 and MIP-1α could both enhance T cell survival and proliferation and recruit more T cells and innate immune cells such as macrophages to the tumor, respectively.…”

New insights into IL-12-mediated tumor suppression

“…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.…”

“…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.…”

Enhancing the safety of antibody-based immunomodulatory cancer therapy without compromising therapeutic benefit: Can we have our cake and eat it too?

“…For instance, CD40 ligation on DCs induces secretion of IL-12 110 , which facilitates beneficial tumoricidal effector T cell function 158 , but when present at high systemic levels can be toxic 159 . Perhaps the most dramatic example of this type of irAE occurred during a phase I clinical trial evaluating the safety of TGN1412, a superagonist to CD28 that had been designed to activate Tregs, but unfortunately ended in disaster when all six trial participants in the treatment group rapidly developed symptoms characteristic of cytokine release syndrome (cytokine storm involving rapid spikes in systemic TNF-α, IFN-γ, IL-6, IL-2, IL-1β and others, as illustrated in Fig.…”