Chronic lymphocytic leukemia (CLL) is associated with profound suppression of the humoral, innate, and cellular components of the immune system. CLL cells are transformed B lymphocytes but lack classic co-stimulatory molecules typically present on normal B cells. The lack of co-stimulatory molecules on CLL cells, along with the production of soluble cytokines that dampen T-cell function, at least in part explain why autologous or even allogeneic T cells do not promote cytotoxicity toward these "stealth-like" tumor cells. To address this issue, Kipps and colleagues developed a strategy in which an adenovirus encoding the co-stimulatory molecule CD154 is used to infect CLL cells ex vivo. The enhanced CD154 expression on CLL cells produces an activated B-cell phenotype that promotes T-cell activation.1 This results in T-cell recognition and cytolysis of CLL tumor cells in vivo, even those that did not encounter the virus. After extensive pre-clinical work and regulatory hurdles due to the increased concern over gene therapy trials, this group initiated a phase I study employing this approach that showed promising early and delayed anti-tumor responses.2 Additionally, broad evidence of immunologic activation of T cells was noted, together with enhanced sensitivity of CLL cells to activation-induced cell death mediated by p73.3,4
As a follow-up to this study, Dr. Kipps’ laboratory has now identified that a subset of CLL patients treated with this therapy developed "self" monoclonal antibodies directed at the tumor antigen ROR1A. Following identification of ROR1A as an autologous self antigen, the authors went on to demonstrate that this antigen is not expressed on normal B cells or other tissues in patients with CLL. Additionally, ROR1A appears to signal through WNT5a and NF-κB. Here the story becomes more complex, as CLL cells do not express WNT5a. However, WNT5a is expressed by accessory dendritic cells, which potentially provide stromal support to CLL tumor cells. Evidence for a stromal interaction of ROR1A and WNT5a is provided by demonstration that co-culture of CLL cells with a WNT5a-expressing cell line enhances survival, whereas addition of a ROR1A blocking antibody antagonizes survival. The relevant in vivo accessory cell remains to be identified, but this finding emphasizes the importance of the microenvironment in providing survival signals to leukemia cells. These results also provide a potential mechanism for the death of transformed B cells long after therapy and possibly explains the prolonged disease stabilization experienced by many patients following treatment with CD154 gene therapy.2 Furthermore, this work constitutes one of the first demonstrations in CLL of a safe therapy to break immunologic tolerance against a "self tumor antigen."5 Without persistent bedside-to-laboratory translational research, this observation would have been lost.
In Brief
Clinical investigation in the area of gene therapy is quite difficult, and before undertaking such an approach for phase II-III studies, it is clearly important to have a strong indication that this strategy could truly benefit patients long-term. The identification of induction of ROR1A antibodies in CLL patients receiving CD154 gene therapy as described in this paper provides such encouragement and shows that this line of clinical investigation warrants further pursuit.2 A clinical trial using the human CD154 gene via a similar adenovirus vector has completed phase I investigation5 and will move forward to phase II testing soon. The strategy of enhancing CD154 expression in CLL cells using gene therapy or another method has exciting potential for the treatment of CLL. Furthermore, the use of ROR1A-directed therapeutic antibodies against CLL cells represents an option that should be actively pursued based upon the data presented in this paper and others.6 Most importantly, the paper by Kipps and colleagues highlights the great value of rigorous bedside-to-laboratory translational investigations of novel therapies. Such detailed correlative work that allows understanding of the mechanism of action of a new therapeutic agent should be included in virtually all clinical trials of targeted agents, so that expected (and more importantly, unexpected) findings, such as the induction of ROR1A antibodies noted in this report, can be discovered.
References
Competing Interests
Dr. Byrd indicated no relevant conflicts of interest.
