This clinical trial design provided a unique opportunity to assess whether prior therapy with sorafenib might adversely affect IL-2-induced signal transduction within T cells. This correlative readout is of interest as prior in vitro studies from our group have indicated that a pretreatment with sorafenib may inhibit the subsequent cellular response to IL-2 stimulation ex vivo.17 For these studies, blood samples were available from 6 patients before and after sorafenib administration. The percentage of CD4+ and CD8+ T cells with pSTAT5 was assessed at baseline and 1 hour after IL-2 stimulation during series 1 and series 2. Consistent with prior studies by our group,19 the percentage of CD4+ and CD8+ T cells with pSTAT5 1 hour after IL-2 infusion was elevated as compared with baseline during both series 1 and 2. There was no significant difference in the percentage of pSTAT5-positive CD4+ or CD8+ T cells after IL-2 during series 1 versus series 2 (all P>0.4, Fig. 4). These data suggest that prior therapy with sorafenib may not adversely affect STAT5 signal transduction in T cells after subsequent IL-2 administration. We did not perform the same analysis in individuals who did not go on to receive a second series.
We have shown that the combination of HD IL-2 and sorafenib as studied is feasible and safe. An abundance of caution led to the phase I design which was deemed necessary due to the potential for unforeseen overlapping or additive toxicities even though the agents were not administered simultaneously. Indeed, concern for serious cardiac toxicity in patients treated in nontrial settings with HD IL-2 following VEGF TKI’s was raised during the conduct of this trial.24 This was not observed in this trial. It is interesting to note that the toxicities during the second series (HD IL-2 after sorafenib) were numerically less than with the first series. This observation is certainly affected by selection bias. In retrospect, different schedules including a concurrent schedule may also have been safe. Early phase trials suggested clinical benefit with sorafenib in MM.25 This study was open and accruing participants before the completion of subsequent studies that showed a lack of clinical activity for sorafenib in MM. Concern for sub optimal dosing in these studies has been expressed.26,27
The biomarkers that account for clinical activity associated with HD IL-2 are likely multifactorial and involve changes in multiple immune effector cell compartments or the tumor microenvironment. The study design of the present trial allowed for a unique opportunity to evaluate the effect of prior sorafenib on IL-2-induced pSTAT5 in T cells at a number of prespecified timepoints. Prior preclinical studies from our group indicated that this canonical IL-2 signaling pathway might be inhibited by pretreatment of immune cells with sorafenib, and possibly compromise antitumor effects of exogenous IL-2.17 The data generated in this trial provided preliminary evidence that intracellular IL-2 signaling remained intact in patient T lymphocytes after a course of sorafenib treatment. The lack of an inhibitory effect of sorafenib on T-cell signaling is likely due to the schedule used, whereby the effects of sorafenib-mediated TK inhibition in T cells normalize before subsequent IL-2 therapy.
Because of its multitargeted nature at the level of TK inhibition, sorafenib may have inhibitory effects upon Treg cells or MDSC, which rely on cytokine signals to maintain homeostasis and function. We hypothesized that downregulating tumor-associated immunosuppression through sorafenib may enhance the immune-mediated antitumor effects of IL-2. However, sorafenib exposure followed by HD IL-2 had no significant effect on the percentage of circulating natural Treg cells (CD4+, CD25+, FoxP3+) or cells with phenotypic properties consistent with MDSC (HLADRIo, CD11b+, CD33+) using the schedule used in this trial. Clearly, analysis of immunosuppressive cell populations was somewhat limited in this trial, as more recently other relevant cell populations have received attention in advanced cancer patients including inducible Treg cells or MDSC expressing the CD14+ marker, among others. Because of limited availability of blood samples and ability to biopsy patients on this trial, the effects of this regimen on immune biomarkers in the tumor microenvironment were not evaluable.
CRs were not observed in our trial and we therefore do not know if sorafenib inhibited better responses. The partial responses suggest otherwise. Although not demonstrated in this small phase I trial, the potential remains that active single agents may affect the tumor’s ability to suppress the immune response and therefore lead to enhanced benefit from immunotherapy such as HD IL-2. We have demonstrated a schedule that is both feasible and safe. However, the small size of the trial and the highly selected group of relatively young and fit IL-2-eligible patients represent major limitations when attempting to generalize to larger populations with MM or RCC.
HD IL-2 remains relevant due to the remarkably durable CRs seen in a select few. In the nearly 20 years since HD IL-2 was approved by the FDA for the treatment of MM and RCC, several investigators have attempted clinical trials combining HD IL-2 with other agents.28–33 These studies demonstrated that the combination was feasible; however, the agents chosen to combine with HD IL-2 had very little single-agent activity. Sorafenib is one of the first in an expanding category of distinct but related agents. Its single-agent activity and nonoverlapping toxicity profile led us to perform this combination trial with HD IL-2. To the best of our knowledge, this is the first report of sorafenib or any other VEGF-TKI being combined with HD-IL-2. Sorafenib combined with lower dose subcutaneous IL-2 has been reported to be safe with no increase in efficacy compared with sorafenib alone.34 Given the safety of our treatment schedule, a phase II trial of this combination seems reasonable. We acknowledge that since this trial was initiated, there exists renewed enthusiasm for immune-based therapy based on new understanding and favorable clinical trial outcomes.35,36
Sorafenib when combined with HD IL-2 in the schedule evaluated was not associated with unexpected toxicity and no DLT was seen. Further study of sorafenib or other promising agents using a similar schedule combined with HD IL-2 seem warranted.
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