A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma

Abstract

PurposeIntratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 combination and to obtain data on clinical efficacy.ResultsThere was no dose limiting toxicity. While local response of injected lesions was observed in 67% patients (95% CI, 40%-93%), an abscopal response was seen in 89% (95% CI, 68%-100%). The overall response rate and clinical benefit rate by immune-related response criteria (irRC) was 40% (95% CI, 10%-70%) and 50% (95% CI, 19%-81%), respectively. Enhanced systemic immune response was observed in most patients and correlated with clinical responses.Experimental DesignTwelve patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3 design was employed to assess highest tolerable intratumoral dose of ipilimumab and IL-2 based on toxicity during the first three weeks. Escalated doses of ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of three patients. A fixed dose of IL-2 was injected three times a week into the same lesion for two weeks, followed by two times a week for six weeks.ConclusionsIntratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients.

Immune and molecular correlates in melanoma treated with immune checkpoint blockade

“…Clinically, for example, the combination of intratumoral injection of IL-2 with anti-CTLA4 appeared to produce responses in a phase 1 trial. 37 In summary, each of these molecular and cellular markers is linked to the others, and all have been correlated to some extent with checkpoint-inhibition response. Although PD-L1 expression, MHC expression, and mutational load all certainly play a part in the molecular mechanism underlying the success or failure of checkpoint blockade, they are linked in a network that is not yet fully understood and likely involves many other components of immune signaling.…”

“…Many more factors also contribute to this environment. Clinically, for example, the combination of intra-tumoral injection of IL-2 with anti-CTLA4 appears to produce responses in a phase 1 trial 37 . In summary, each of these molecular and cellular markers is linked to the others, and all have been found to correlate, to some extent, with checkpoint inhibition response.…”

Designing In and Around Tolerability Considerations for Immunotherapy Combinations

“…Additional recent investigations of intratumoral IO combinations also include IPI administered with interleukin-2 (IL-2) in advanced melanoma. 9 However, unlike these previous examples, not all tumors are as accessible for direct administration, and local administration to tumors does not preclude at least some leakage back to the systemic circulation.…”

“…Intravesical BCG immunotherapy is now indicated for carcinoma in situ of the bladder, and is under investigation in combination with other agents, including the PD‐L1 inhibitor atezolizumab (http://ClinicalTrials.gov Identifier: NCT02792192) which is administered intravenously. Additional recent investigations of intratumoral IO combinations also include IPI administered with interleukin‐2 (IL‐2) in advanced melanoma . However, unlike these previous examples, not all tumors are as accessible for direct administration, and local administration to tumors does not preclude at least some leakage back to the systemic circulation.…”

Intrapleural immunotherapy: An update on emerging treatment strategies for pleural malignancy

“…Cytokine‐based immunotherapies have shown promise as potent immunostimulatory agents applied to counter tumor‐mediated immune tolerance and T‐cell exhaustion. Interleukin 2 (IL‐2) in particular has been applied in a number of local paradigms to generate tumor‐specific immune responses including in the management of MPE. Hu et al conducted a trial of the use of intrapleural recombinant human IL‐2 in the management of MPE because of lung cancer, specifically analyzing the counter‐regulatory effect of IL‐2 on pleural CD8 + T‐cell activity .…”