Rapid complete response of metastatic melanoma in a patient undergoing ipilimumab immunotherapy in the setting of active ulcerative colitis
© The Bostwick et al.; licensee BioMed Central. 2015
Received: 15 December 2014
Accepted: 24 April 2015
Published: 19 May 2015
While blockade of the cytotoxic T-lymphocyte antigen-4 (CTLA-4) T cell regulatory receptor has become a commonly utilized strategy in the management of advanced melanoma, many questions remain regarding the use of this agent in patient populations with autoimmune disease. We present a case involving the treatment of a patient with stage IV melanoma and ulcerative colitis (UC) with anti-CTLA-4 antibody immunotherapy. Upon initial treatment, the patient developed grade III colitis requiring tumor necrosis factor-alpha (TNF-α) blocking antibody therapy, however re-treatment with anti-CTLA-4 antibody following a total colectomy resulted in a rapid complete response accompanied by the development of a tracheobronchitis, a previously described extra-intestinal manifestation of UC. This case contributes to the evolving literature on the use of checkpoint inhibitors in patients also suffering from autoimmune disease, supports future clinical trials investigating the use of these agents in patients with autoimmune diseases, and suggests that an understanding of the specific molecular pathways involved in a patient’s autoimmune pathology may provide insight into the development of more effective novel combinatorial immunotherapeutic strategies.
KeywordsIpilimumab Advanced melanoma Ulcerative colitis Autoimmunity
Ipilimumab is a humanized IgG monoclonal antibody that blocks the negative regulatory receptor CTLA-4 on the surface of activated T cells . While ipilimumab has been demonstrated to effectively promote the activation of effector CD8+ T cells, recent studies have revealed this agent to also deplete regulatory T cell populations which contribute to the establishment of an immunotolerant tumor microenvironment [2,3]. Almost 25 years after the CTLA-4 gene was cloned, clinical studies showing ipilimumab to significantly prolong overall survival in patients with advanced melanoma earned this agent FDA approval in March of 2011 . While ipilimumab has been associated with a disease control rate of ~25%, treatment with this agent has also been associated with a number of immune-related adverse events including enterocolitis (30-33%), dermatitis (40-43%), hepatitis (3-9%) and autoimmune lymphocytic hypophysitis with anterior panhypopituitarism (1-6%) [5,6]. As evidence that anti-CTLA-4 antibody blockade effectively induces the activation of self-reactive T cells in melanoma patients, studies have associated the induction of autoimmune side-effects with clinical response . Due to the potential for inducing these autoimmune side-effects, there is significant apprehension regarding the use of this agent in patients with underlying autoimmune disease . Given these concerns, there is limited information available regarding the administration of ipilimumab in this clinical setting. A small number of recent case reports have described the administration of ipilimumab to patients with concomitant autoimmune disorders, specifically multiple sclerosis, rheumatoid arthritis, and ulcerative colitis without related exacerbation [8,9]. Here, we wish to add to these reports by describing a patient with known ulcerative colitis who was successfully treated with ipilimumab immunotherapy. While this patient initially developed grade III colitis following his first dose of ipilimumab (3 mg/kg), he later established a rapid complete response to re-treatment with ipilimumab following a total colectomy. In addition, upon re-treatment with the complete four dose regimen of ipilimumab following the colectomy procedure, the patient manifested side-effects consistent with hypophysitis, dermatitis, as well as tracheobronchitis, a condition previously described to occur more frequently in patients with inflammatory bowel disease [10,11].
We describe a patient with active ulcerative colitis who underwent treatment with ipilimumab immunotherapy for progressive stage IV melanoma due to limited treatment alternatives. Though the patient experienced a life threatening exacerbation of his ulcerative colitis with administration of ipilimumab, after a total colectomy the patient achieved a marked response to ipilimumab immunotherapy and is, to this date, without evidence of disease. While most patients that ultimately obtain a CR in response to ipilimumab therapy at a dose of 3 mg/kg exhibit relatively rapid objective responses, previous long-term follow-up studies have found patients to require an average of 30 months before obtaining a technical CR . Therefore, this case report describes a rapid response to ipilimumab given the documented CR reported within 6 months of initiating ipilimumab immunotherapy. While the patient never exhibited any signs or symptoms of PSC, he did develop tracheobronchitis and two additional immune-related adverse events (irAE) including a grade I rash and a grade III autoimmune endocrinopathy (anterior panhypopituitarism). The development of a grade III irAE in conjunction with the development of a CR are consistent with prior studies showing a statistically significant association between irAEs and objective response to ipilimumab therapy [12,13]. In addition, this patient also demonstrated a significant increase in his absolute lymphocyte count (ALC), a finding previously noted to correlate with clinical response to ipilimumab (Figure 2B) .
The development of a grade IV irAE in a UC patient receiving ipilimumab therapy substantiates previous concerns regarding the use of CTLA-4 blockade in this patient population and emphasizes the need for close clinical monitoring of patients with autoimmune diseases undergoing any form of immunotherapy. This report also raises the concept of a prophylactic colectomy in patients with active inflammatory bowel disease prior to undergoing anti-CTLA-4 antibody therapy. While this approach was discussed following his initial treatment with ipilimumab and repeat hospitalizations for grade III colitis, this was felt to be associated with an unacceptably high risk-benefit ratio given the lack of available data of ipilimumab efficacy in the setting of UC. We acknowledge that this is a single patient experience and is not necessarily applicable to all UC patients that also carry a diagnosis of advanced melanoma. However, given the ultimate outcome of this case, we feel that such an approach should be contemplated on a patient-by-patient basis.
It is tempting to speculate that the altered T cell negative regulatory pathways which have been previously described in UC patients, such as those that modulate the IL-10 receptor signaling pathway, serve to predispose to anti-CTLA-4 antibody-mediated T cell activation and enable a more potent anti-tumor immune response . Whether this patient harbors a genetic mutation that directly impacts effector T cell function is currently unknown. It is also not clear whether patients with specific types of autoimmune disease are more likely to respond to anti-CTLA-4 antibody therapy. Given the various molecular mechanisms that have been identified among patients with the same clinical diagnosis, we hypothesize that patient responses to CTLA-4 blockade are more likely to associate with specific molecular alterations rather than the clinically diagnosed autoimmune disease.
This case report serves to contribute to the limited literature describing the use of an immune checkpoint inhibitor in a patient with an active autoimmune disease and advocates for future clinical trials investigating these agents in this patient population in a controlled setting. We also propose that an understanding of the molecular mechanisms underlying the autoimmune disease of patients who have generated significant responses to anti-CTLA-4 therapy could lead to the identification of novel combinatorial immunotherapy regimens with enhanced clinical efficacy.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. Copies of the written consents are available for review by the Editor-in-Chief of this journal.
Cytotoxic T-lymphocyte-associated antigen-4
Immune-related adverse event
Tumor necrosis factor-alpha
Absolute lymphocyte count
- PET CT:
Positron emission tomography-computed tomography
B.A.H. received a Young Investigator Award from the Melanoma Research Alliance.
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