Prof G what happens to MS disease activity if you stimulate T-cells?
About 2 years ago I attended a grand round during which a patient with a history of RRMS had had a catastrophic relapse after receiving ipilimumab for metastatic melanoma. The patient has a massive brain stem relapse and her MRI showed multiple Gd-enhancing lesions with several pseudotumoral lesions. She was in a bad way. Interestingly, this case was not unique as a very similar case had been published. In addition, there are series of other examples of ipilimumab and other immune checkpoint inhibitors exacerbating and/or triggering autoimmune diseases including an MS-like disease. I say MS-like because we don’t know for sure if these cases will turn out to have classic MS on biopsy, or at post-mortem, to prove they have definite MS according to a conventional definition of the disease.
Ipilimumab belongs to the class of drugs called ‘checkpoint inhibitors’ that are designed to remove one of the immunological brakes that control T-cell activation. Ipilimumab is one of many T-cell stimulants that have revolutionised the care of patients with various different cancers. Ipilimumab is a very smart drug it blocks CTLA-4, a cell surface molecule on T cells, which normally blocks or downregulates T cell activation when it binds to CD80 and CD86 on antigen-presenting cells. Ipilimumab enhances the anti-tumoral response while increasing the likelihood of autoimmunity.
So what has this really got to do with MS? Well, these cases are telling us in a not so subtle way that by stimulating T-cells we can exacerbate MS. In other words, T-cells are probably still active in established MS. What this experiment is not telling us is which population of T-cells is the culprit as CD4+, CD8+ and T-regulatory cells express CTLA-4 and are hence affected by Ipilimumab. Nor is it telling us about the APC side, which APC is stimulating the T-cells. Is it the B-cell, the macrophage/microglia or another APC?
The moral of this story is that it takes two to tango; the T-cell and its APC. The question is which APC is the preferred partner for the T-cell in MS. Based on the evidence the B-cell seems to be the dominant partner, but who knows in the presence of peripheral B-cell depletion other less dominant partners may take to the floor.
Gettings et al. Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma. Mult Scler. 2015 Apr;21(5):670.
56-year-old male, diagnosed in December 1997 with RRMS. Treated with glatiramer acetate in February 1998. Relatively good response to GA with only sensory relapses. In 2005 methotrexate was added. His MS stabilized and he was free of relapses from 2005 to 2013 with a slight increase in disability from an Expanded Disability Status Scale (EDSS) score of 1 to 1.5. In September 2009 diagnosed with melanoma. He had a recurrence in November 2012 with metastases to soft tissue and lymph nodes. He was started on ipilimumab. Methotrexate and glatiramer acetate were stopped prior to initiating ipilimumab. Within one month, he presented with subacute onset of left lower extremity hemiparesis, gait dysfunction and ataxia. An MRI revealed a new left centrum semiovale enhancing lesion consistent with active demyelination. His symptoms improved with high dose methylprednisolone. Ipilimumab was continued. In May 2013 he was readmitted for transient left-sided weakness and ataxia. MRI revealed an enhancing lesion in the right corona radiata. Follow-up imaging revealed a second enhancing lesion in the right frontal lobe and he was restarted on glatiramer acetate and steroids.