Worsening of Autoimmunity

Johnson DB, Sullivan RJ, Ott PA, Carlino MS, Khushalani NI, Ye F, Guminski A, Puzanov I, Lawrence DP, Buchbinder EI, Mudigonda T, Spencer K, Bender C, Lee J, Kaufman HL, Menzies AM, Hassel JC, Mehnert JM, Sosman JA, Long GV, Clark JI. Ipilimumab Therapy in Patients With Advanced Melanoma and Preexisting Autoimmune Disorders. JAMA Oncol. 2015 Dec 3:1-7. doi: 10.1001/jamaoncol.2015.4368. [Epub ahead of print]4

IMPORTANCE:Ipilimumab and other immune therapies are effective treatment options for patients with advanced melanoma but cause frequent immune-related toxic effects. Autoimmune diseases are common, and the safety and efficacy of ipilimumab therapy in patients with preexisting autoimmune disorders is not known.
OBJECTIVE:To determine the safety and efficacy of ipilimumab therapy in patients with advanced melanoma with preexisting autoimmune disorders.
DESIGN, SETTING, AND PARTICIPANTS:Retrospective review of patients with advanced melanoma and preexisting autoimmune disorders who received ipilimumab at 9 academic tertiary referral centers from January 1, 2012, through August 1, 2015. The data analysis was performed on August 24, 2015.
EXPOSURE:Ipilimumab therapy.
MAIN OUTCOMES AND MEASURES:Safety, in terms of frequency of autoimmune flares and conventional immune-related adverse events (irAEs), and efficacy, in terms of response rates and overall survival, were evaluated descriptively.
RESULTS:Of the 30 patients who received ipilimumab (17 [57%] male; median [range] age, 59.5 [30-80] y), 6 had rheumatoid arthritis, 5 had psoriasis, 6 had inflammatory bowel disease, 2 had systemic lupus erythematosus, 2 had multiple sclerosis, 2 had autoimmune thyroiditis, and 7 had other conditions. Thirteen patients (43%) were receiving immunosuppressive therapy at the time of initiation of ipilimumab therapy, most commonly low-dose prednisone or hydroxychloroquine. With ipilimumab treatment, 8 patients (27%) experienced exacerbations of their autoimmune condition necessitating systemic treatment; all were managed with corticosteroids. Conventional grade 3 to 5 irAEs occurred in 10 patients (33%) and were reversible with corticosteroids or with infliximab therapy in 2 cases. One patient with baseline psoriasis died of presumed immune-related colitis after a 1-week delay prior to reporting symptoms. Fifteen patients (50%) had neither autoimmune disease flares nor irAEs. Six patients experienced an objective response (20%), including 1 with a durable complete response.
CONCLUSIONS AND RELEVANCE:To our knowledge, this is the largest series of patients with pre-existing autoimmune disease treated with immune checkpoint inhibitors. Ipilimumab was clinically active and was associated with exacerbations of autoimmune disease and conventional ipilimumab-induced irAEs that were readily manageable with standard therapies when started in a timely fashion. Ipilimumab therapy may be considered in this setting with vigilant clinical monitoring.

Failures can sometimes tell us as much as successes. In this study they look at an antibody that blocks CTLA. This is a regulator of T cell activation. CTLA4 or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 CTLA4 is found on the surface of T cells, and acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.Conversely, there is increasing interest in the possible therapeutic benefits of blocking CTLA4 (using antagonistic antibodies against CTLA such as ipilimumab (FDA approved for melanoma in 2011) as a means of inhibiting immune system tolerance to tumours and thereby providing a potentially useful immunotherapy strategy for patients with cancer. However it could block tolerance to autoimmunity and it is therefore that whilst treating these skin cancers, a few people with additional autoimmunity where treated and a number of people go
t worse. This can indicate that autoimmunity is at the centre of MS succeptibility