Tackling T-cell tumors

Cutaneous T-cell lymphomas represent a tumor with a defined target, the somatically rearranged T-cell receptor (TCR), that should represent a tumor-specific immunologic target analogous to the idiotype (Id)-specific target of B-cell lymphomas. The Id antigen on B-cell lymphomas has been targeted by Levy and others using a variety of vaccine approaches and large prospective clinical trials of this strategy are ongoing. The secreted antibody associated with myeloma has also been demonstrated to be processed and presented on malignant B cells and could be recognized by antigen-specific T cells.¹  Although much less common than B-cell malignancies, the TCR on T-cell malignancies also represents an attractive immunotherapy target. Unfortunately, the TCR is not secreted and capturing the antigen from an individual's tumor for the creation of a vaccine usually involves creating a whole tumor lysate.FIG1 

Maier and colleagues (page 2338) performed this experiment, vaccinating 10 cutaneous T-cell lymphoma patients with tumor lysate pulsed onto autologous dendritic cells (DCs) loaded with tumor lysate and given by intranodal injection.²  Intranodal injection appears to be a important route of delivery since the initial observation that intravenous and subcutaneous delivery in humans lead to little trafficking to lymph nodes, whereas only a fraction of DCs injected into the dermis trafficked to draining lymph nodes.³ 

In this report, Maier and colleagues have shown the induction of antigen-specific T-cell responses and clinical response in patients with cutaneous T-cell lymphoma. The authors noted that delayed-type hyper-sensitivity to the tumor lysate was increased in treated patients and recognition of autologous tumor cells by peripheral blood mono-nuclear cells (PBMCs) following vaccination compared with PBMCs obtained prior to vaccination as determined by cell proliferation and cytokine release assays. Significant recognition was notable in 3 patients, all of whom had a clinical response (1 complete and 2 partial responses). One element that was not specifically addressed by this study was whether an immune response to the specific TCR of each tumor was induced.

Nonetheless, the potential to target malignant T-cell tumors is demonstrated in this pilot study. The feasibility and utility of DC vaccination by the intranodal route is again highlighted. Finally, the correlation of autologous tumor-specific immune responses with clinical responses is provocative. The authors did not demonstrate specific immune responses against the TCR of each tumor, a finding that would have important indications for the treatment of this malignancy but also for the therapeutic elimination of T-cell clones in autoimmune disorders. Further investigation of immunotherapy in this promising model system is certainly warranted.