When are signal transduction targeted therapies acting as immunotherapy?

Abstract

 

Keywords:

• BRAF inhibitor
• interleukin-2
• ipilimumab
• melanoma
• synergy

Despite a dizzying rate of therapeutic advances for metastatic melanoma over the past 5 years, the majority of patients are still succumbing to their disease. Novel immune therapies, with inhibitors of immune checkpoints as the most impactful at a population level, are broadly relevant across the metastatic melanoma population and produce apparently permanent disease control/response in a minority of patients.^1,2 However, adoption of these therapies into routine clinical practice has created the view that these agents are most effective in patients with low disease burden or indolent disease kinetics. Signal transduction targeted therapy has gained the greatest traction in BRAF mutant melanomas, which account for approximately 40–50% of the entire population. Combined BRAF/MEK targeted therapy can produce profound tumor regressions even in patients with high disease burden and rapid growth kinetics, but with highly variable duration. ³ Nascent efforts to establish the benefit of MAP kinase pathway targeted therapy in other genetically-defined melanoma subsets are still in progress.

A major area of interest in the field currently is the development of combination regimens that are able to leverage the rapid and confident disease control features of BRAF inhibitor-based therapy with the long-term impact of immune checkpoint inhibitors. On purely clinical grounds, a case can be made for the imperative of resolving combination or rapid sequential approaches with cytotoxic (signal transduction targeted therapies in the case of melanoma) with immunologic treatments.

Multiple lines of evidence support a potential mechanistic intersection between MAP kinase pathway targeted therapy and immune therapy, at least in BRAF mutant cancers. Two groups have shown that BRAF inhibitors alone or in combination with MEK inhibitors are associated with a consistently increased infiltration of CD8+ T cells into tumor when biopsies before and early during the course of therapy. ^4,5 Additionally, melanocyte lineage antigen presentation appears to increase consistently in an MITF dependent fashion in both experimental models and in patients.⁴ And, exposure of autologous T cells to tumor cells in the presence of BRAF inhibitor ex vivo promotes, not inhibits, T cell activation, proliferation and production of interferon gamma.⁶ While these observations point toward a largely positive immunologic effects, there is evidence that some tumor upregulate expression of PD-L1, which could promote continued escape from immune surveillance. While mechanistic underpinnings of these phenomena await further clarification, they support the concept that synergy may be achievable with signal transduction and immune checkpoint inhibitor therapy.

Wyluda and colleagues³ intriguing cases of patients who were treated serially with high-dose interleukin-2, followed by ipilimumab in the presence of disease progression, and then BRAF inhibitor monotherapy, again triggered by disease progression[Wyluda et al. CB&T 2015]. In each case, complete responses were observed which were ongoing at the time of this report (up to 15 months for the patient with longest follow-up). Certainly, complete response to BRAF inhibitor monotherapy are an uncommon event (approximately 5% from large-scale phase II and III trials of vemurafenib and dabrafenib). So, the statistical likelihood of having 3 consecutive patients achieve complete response is low (about 0.01%). Though not detailed their report, these 3 cases are almost certainly among a far larger number of patients treated with BRAF inhibitors by this group. One wonders what sets these patients apart. First, were these the only patients to have received sequential IL-2, ipilimumab and BRAF inhibitor? Second, are these patients immunologically unique by virtue of the fact that 2 of the 3 developed autoimmune hypophysitis and the third had baseline “mild” systemic lupus erythematosus. Hypophysitis is both an uncommon (though not rare) complication of ipilimumab, but is also strongly associated with survival impact from that agent. So, even in the absence of early response to ipilimumab, is it possible that the 2 patients were having the type of immune response that would have translated into benefit even in the absence of initiating BRAF inhibitor therapy? Did the use of both IL-2 and ipilimumab contribute to setting the stage for BRAF inhibition to instill a cytotoxic effect that triggered enhanced immune recognition? A subset analysis of an ipilimumab phase III trial suggested that the small minority of patients who received IL-2 prior to enrolling on the trial fared somewhat better than patients who had not had prior IL-2 therapy.¹ This is, of course, a potentially confounded observation.

Despite several unknown and currently unanswerable aspects of these 3 cases with most desirable outcomes, there are intriguing features to these cases that contribute to the already heightened interest in signal transduction targeted/immunotherapy combinations. The authors place substantial emphasis of the apparent inflammatory arthritis induced by BRAF inhibitor therapy in one case and protracted arthralgia in another. Arthralgia is a very common toxicity from vemurafenib, in particular.⁷ And, cases of inflammatory arthritis have certainly been observed in patients who have never been treated with prior immune therapy. However, such events generally resolve rapidly with drug holding and do not necessitate regular one week breaks from treatment, such as were utilized in these cases. One wonders whether this unique schedule of administration contributed to the durability of response observed thus far, as preclinical data support the concept of interrupted schedule as a way of forestalling emergence of resistance.⁸

The immune monitoring performed in peripheral blood is interesting from the perspective of defining a pattern that could be sought for subsequent patients receiving sequential or concomitant targeted and immune therapies. However, by virtue of being blood-based and enumerating entire T cell subsets, as opposed to those with cytolytic activity against tumor, these studies cannot be taken as mechanistic proof that BRAF inhibitor treatment truly invoked an immune response that was not already operant in the tumor following ipilimumab.

The mechanistic intersection of immune therapy followed by tumor-directed, signal transduction targeted therapy is hypothesized to relate to tumor cell killing and presentation by dendritic cells to primed T cells. The same concept has been developed for use of high-dose, hypofractionated radiation therapy targeting an individual tumor in patients with widespread metastatic disease who have recently received or are in the midst of receiving immunotherapy.⁹ Clinical validation of this approach is still lacking. And careful ascertainment of T cell repertoire in tumor and blood prior to, during and following such perturbations has not yet been performed.

In these case, patients received 2 courses of immune therapy (presumably requiring 4–5 months to administer) prior to initiation of BRAF inhibitor therapy. The majority and even vast majority of patients with metastatic melanoma cannot survive and remain good candidates for treatment for 4–5 months without a response to treatment. Thus, this specific strategy would likely only pertain to patients with low disease burden or slow progression kinetics. If IL-2 was an important component of this sequential therapy, then the physiologic stresses of that therapy would place a further filter on the subpopulation of patients who could undergo this specific sequence of therapy. For this strategy to be more broadly applicable it would be critical to understand if checkpoint inhibitor alone could be followed by BRAF inhibition. And, with the onset of action of ipilimumab being still poorly understood in humans, the optimal timing of BRAF inhibitor initiation is critical to work out. In these cases, the use of BRAF inhibitor only after documentation of disease progression heightens the possibility that these patients were truly failing ipilimumab (and not on the verge of manifesting a delayed response). But, the concept might be more widely applicable if initiation of the BRAF inhibitor could be moved to midcourse in ipilimumab induction.

Lastly, one wonders whether the observed effects with ipilimumab could be extended to the more PD-1/PD-L1 antibodies which are associated with a higher response rate and somewhat more rapid onset of action.¹⁰ For those patients with the highest disease burden and rapid progression kinetics, simultaneous initiation of both signal transduction and immune therapy may represent the only tractable approach to evaluate in clinical trials and adopt in clinical practice (if more effective than sequential therapy). For the reasons of minimizing toxicity from such concomitant therapies, the authors rightfully endorse the approach of sequential therapy if their impressive experience in these 3 cases can be reproduced on large scale.

Disclosure of Potential Conflicts of Interest

Dr. Flaherty has served as a consultant to GlaxoSmithKline, Novartis, Roche, and Merck.