We describe three consecutive patients treated with overlapping standard dosing of anti-PD-1-directed therapy and HD IL-2. All patients had previously progressed on multiple prior treatments including anti-PD-1-directed therapies. None of the patients experienced unusual or excessive side effects from the combination therapy as compared with toxicities expected from HD IL-2 alone. The average number of doses of IL-2 reflects the toxicity and tolerability. Contemporary data in ipilimumab refractory patients found on average of nine doses for cycle 1 and eight doses for cycle 2 [
5]. Despite these three patients’ multiple prior treatments and each with significant preexisting comorbidity (atrial fibrillation, adrenal insufficiency, and severe pulmonary hypertension), our patients experienced similar number of doses with cycle 1 (9, 11, 8) and cycle 2 (9, 10, 9). The number of doses is also consistent with our institutional average of ten doses in cycle 1 and nine doses in cycle 2 during course 1 of therapy (unpublished internal data). The dose-limiting toxicities were primarily cardiac, pulmonary, or neurologic, which also fits with our internal database of HD IL-2 administration. Thus, concurrent dosing of standard HD IL-2 with anti-PD-1 in heavily pretreated patients appears feasible at experienced centers.
There are many novel treatments for metastatic melanoma [
6], but identifying additional new combination therapies is particularly important in checkpoint-resistant patients because approximately half of all metastatic melanoma patients progress on current standard treatments. A combination of anti-LAG-3 and PD-1 inhibition was recently approved based on improved progression-free survival data from NCT03470922, with objective response and overall survival data pending [
7]. Response rates to HD IL-2 historically ranged from 15% to 23% with 5–10% complete responses [
4,
5]. Patients resistant to PD-1 blockade appear to maintain the same historical response rate seen with HD IL-2 compared with therapy-naïve patients (roughly 20%) [
4]. Several mechanisms may govern resistance to PD-1 inhibitors, including lack of an inflammatory response, activation of other checkpoints, loss of antigen expression, and the development of T cell exhaustion. IL-2 can address many of these barriers. In addition, IL-2 augments memory T-cell differentiation and responses and increases natural killer cells [
3]. In mouse models, administering IL-2 in combination with anti-PD-L1 blockade showed synergistic increases in antigen-specific CD8 T cell numbers and function [
8]. Targeting the PD-1 pathway has the potential to reverse T cell exhaustion, but is not always effective [
9]. A recent randomized clinical trial (NCT03635983) utilizing a βγ-biased pegylated IL-2 formulation in combination with PD-1 inhibition compared with anti-PD-1 alone did not meet its primary endpoints, despite success with the combination in earlier phases [
10]. It is possible that signaling through the α subunit of the IL-2 receptor is necessary to achieve a sufficient level of anticancer immune response. The possibility that the combination of anti-PD-1 and HD IL-2 may overcome resistance to anti-PD-1-directed therapy has prompted formal exploration in treatment-refractory metastatic melanoma and metastatic kidney cancer patients in NCT03991130.