Do glucocorticoids or dexamethasone reduce the effectiveness of immunotherapy in melanoma???

For years and years the vast preponderance of the evidence has demonstrated that folks with significant side effects to immunotherapy not only NEEDED to be treated with steroids in order to deal with the problem presented, but also (thank goodness!!!) showed that steroid treatment, did NOT decrease their survival/response to immunotherapy itself in the end.  Here is one post with links to zillions of reports on studies that looked at this issue:  For Jubes...and the rest of us!!! An anti-rheumatic drug that increases the effect of vemurafenib and selumetinib????

Now, there's this:

High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma.  Faje, Lawrence, Flaherty.Cancer. 2018 Jul 5.

It remains unclear whether high doses of glucocorticoids have a negative impact on the efficacy of checkpoint inhibitors. To control for the potential association between immune-related adverse events (irAEs) and improved survival, this study examined a unique cohort of patients who had the same irAE treated with varying glucocorticoid doses.
In total, 98 patients with melanoma who had ipilimumab-induced hypophysitis were identified retrospectively in the Partners Healthcare system using an automated electronic medical record query tool. Patients with melanoma who received ipilimumab at Massachusetts General Hospital without developing hypophysitis were listed in an actively maintained institutional patient database. Glucocorticoid doses for patients with hypophysitis were categorized as low dose (LD) or high dose (HD). Survival analyses were performed for patients who received ipilimumab monotherapy.
Both overall survival (OS) and the time to treatment failure were significantly longer in the LD group compared with the HD group. Median OS and the time to treatment failure were not reached in the LD group and were 23.3 and 14.5 months, respectively, in the HD group. All patients who had hypophysitis had improved OS compared with patients who did not have hypophysitis (median, 28.2 vs 9.5 months). This advantage was maintained in the HD group versus the nonhypophysitis group. Radiologic and endocrinologic outcomes and symptom resolution did not differ in the LD group versus the HD group.

Among patients with melanoma who had ipilimumab-induced hypophysitis, those who received higher doses of glucocorticoids had reduced survival. This is the first study to demonstrate a potential negative effect of high glucocorticoid doses on the efficacy of checkpoint inhibitors after an irAE. These findings have potential implications for the management of other irAEs.

So, in this study, in order to avoid muddying the waters in regard to survival due to possible differences in outcome caused by the particular side effect itself, the researchers looked at only one side effect - hypophysitis (inflammation of the pituitary gland, which is located at the base of the brain) after melanoma patients were treated with ipilimumab (Yervoy).  In those 98 patients, some folks were treated with high dose glucocorticoids and others were given a low dose.  In those patients, the low dose folks had an overall survival of 23 months vs only 14 months in the high dose group.  But, to me...here is the bigger news ~ "All patients who had hypophysitis had improved OS compared with patients who did not have hypophysitis (median, 28.2 vs 9.5 months). This advantage was maintained in the HD group versus the nonhypophysitis group."     I do have one question about this study.  Did the folks treated with a higher dose require it in order to deal with their hypophysitis?  Meaning, would a lower steroid dose have been insufficient for an effective response in them?   In the end, despite the fact that these peeps with hypophysitis were treated with steroids....they ALL did better than melanoma peeps with no hypophysitis and no steroids!!!  I think all this reports really tells us is that this pretty horrible side effect seems to come with better survival in melanoma and, of course, we should try to treat side effects using the lowest effective dose of steroids that we can.

Now there is also this (link to entire article and abstract below with thanks to my dear Eric...for sharing it):

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy

Dexamethasone-induced immunosuppression: mechanisms and implications for immunotherapy.  Giles, Hutchinson, Sonnemann, et al.  Journal for Immunotherapy of Cancer, June 11, 2018.

Background: Corticosteroids are routinely utilized to alleviate edema in patients with intracranial lesions and are first-line agents to combat immune-related adverse events (irAEs) that arise with immune checkpoint blockade treatment. However, it is not known if or when corticosteroids can be administered without abrogating the efforts of immunotherapy. The purpose of this study was to evaluate the impact of dexamethasone on lymphocyte activation and proliferation during checkpoint blockade to provide guidance for corticosteroid use while immunotherapy is being implemented as a cancer treatment.

Methods: Lymphocyte proliferation, differentiation, and cytokine production were evaluated during dexamethasone exposure. Human T cells were stimulated through CD3 ligation and co-stimulated either directly by CD28 ligation or by providing CD80, a shared ligand for CD28 and CTLA-4. CTLA-4 signaling was inhibited by antibody blockade using ipilimumab which has been approved for the treatment of several solid tumors. The in vivo effects of dexamethasone during checkpoint blockade were evaluated using the GL261 syngeneic mouse intracranial model, and immune populations were profiled by flow cytometry. 

Results: Dexamethasone upregulated CTLA-4 mRNA and protein in CD4 and CD8 T cells and blocked CD28-mediated cell cycle entry and differentiation. Naïve T cells were most sensitive, leading to a decrease of the development of more differentiated subsets. Resistance to dexamethasone was conferred by blocking CTLA-4 or providing strong CD28 costimulation prior to dexamethasone exposure. CTLA-4 blockade increased IFNγ expression, but not IL-2, in stimulated human peripheral blood T cells exposed to dexamethasone. Finally, we found that CTLA-4 blockade partially rescued T cell numbers in mice bearing intracranial gliomas. CTLA-4 blockade was associated with increased IFNγ-producing tumor-infiltrating T cells and extended survival of dexamethasone-treated mice. 

Conclusions: Dexamethasone-mediated T cell suppression diminishes naïve T cell proliferation and differentiation by attenuating the CD28 co-stimulatory pathway. However, CTLA-4, but not PD-1 blockade can partially prevent some of the inhibitory effects of dexamethasone on the immune response. 

First and foremost, this study was done by looking at cells in a petri dish and poor little real live mice.  And, it seems as though the limiting effects created by dexamethasone (a steroid) on T cells was present when the cells were treated with anti-PD-1 but not when treated with ipi (Yervoy).

Well, damn!  When something seems simple in melanoma....we should realize, "NOPE!  Melanoma gonna be crazy!  You'll see!!!"  Still, these are only two studies among YEARS of other research that indicates treatment of side effects caused by immunotherapy, with steroids, did not diminish the good response in patients with melanoma.  And, like the first report above, we have some indication that side effects may even be an indicator of a good response AGAINST melanoma. Additionally, if you are dealing with a potentially deadly side effect...and you die from it because it went untreated....how good is your outcome going to be then????  However, I do think these results tell us that we should continue to look at this issue and be as conservative in management of side effects with steroids (ie doing so only when really needed and with the lowest effective dose) as possible!

Hang in there ratties!  With melanoma it is always a bumpy ride!!! - c