John G. Gribben

Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-cell function in the chronic lymphocytic leukemia (CLL) Eμ- TCL1 transgenic mouse model. With development of leukemia, Eμ- TCL1 transgenic mice developed functional T-cell defects and alteration of gene and protein expression closely resembling changes seen in CLL human patients. Furthermore, infusion of CLL cells into young Eμ- TCL1 mice induced defects comparable to those seen in mice with developed leukemia, demonstrating a causal relationship between leukemia and the T-cell defects. Altered pathways involved genes regulating actin remodeling, and T cells exhibited dysfunctional immunological synapse formation and T-cell signaling, which was reversed by the immunomodulatory drug lenalidomide. These results further demonstrate the utility of this animal model of CLL and define a versatile model to investigate both the molecular mechanisms of cancer-induced immune suppression and immunotherapeutic repair strategies.

Summary: The humanized anti‐CD52 monoclonal antibody alemtuzumab belongs to the family of Campath‐1 antibodies, which were initially developed for their ability to prevent graft‐versus‐host disease (GVHD) and graft rejection in stem cell transplantation. Alemtuzumab is indicated for the treatment of chronic lymphocytic leukaemia (CLL) and has demonstrated considerable activity in relapsed/refractory disease and in previously untreated disease. It has been shown to induce minimal residual disease‐negative responses as a single agent or as part of consolidation therapy in a meaningful proportion of patients with CLL and has shown promising activity in patients with high‐risk cytogenetic markers. Alemtuzumab may also have significant activity in T‐cell malignancies, such as mycosis fungoides and T‐cell prolymphocytic leukaemia. Recent studies also have evaluated alemtuzumab as part of a conditioning regimen to prevent GVHD in stem cell transplantation. This article reviews our current understanding of alemtuzumab and discusses its emerging role in the treatment of CLL and other haematological malignancies.

Cancer is associated with immune deficiency, but the biologic basis of this is poorly defined. Here we demonstrate that impaired actin polymerization results in CD4⁺ and CD8⁺ T cells from patients with chronic lymphocytic leukemia (CLL) exhibiting defective immunological synapse formation with APCs. Although this synapse dysfunction was in part a result of the CLL cells having poor APC function, defective actin polymerization was also identified in T cells from patients with CLL. We further demonstrate that, following contact with CLL cells, defects in immune synapse formation were induced in healthy allogeneic T cells. This required direct contact and was inhibited by blocking adhesion molecules on CLL B cells. In T cells from patients with CLL and in T cells from healthy individuals that had been in contact with CLL cells, recruitment of key regulatory proteins to the immune synapse was inhibited. Treatment of autologous T cells and CLL cells with the immunomodulating drug lenalidomide resulted in improved synapse formation. These results define what we believe to be a novel immune dysfunction in T cells from patients with CLL that has implications for both autologous and allogeneic immunotherapy approaches and identifies repair of immune synapse defects as an essential step in improving cancer immunotherapy approaches.

Chronic lymphocytic leukemia (CLL) has an extremely heterogeneous clinical course, with some patients requiring immediate therapy and others living without need for treatment for decades. There has been considerable interest in the underlying molecular mechanisms of this heterogeneity to understand not only the expected clinical course for individual patients but also the underlying pathogenesis of this disease. A number of clinical parameters have been identified that are predictive of the clinical course. More recently, a number of molecular biomarkers, most notably cytogenetics by fluorescent in situ hybridization (FISH), immunoglobulin heavy chain (IgVH) mutational status and expression of ZAP70, have been identified and verified as also providing prognostic information. The current challenge is to understand how we should use this new information in clinical practice and whether we should alter treatment based upon the detection of “high-risk” features. Over the past decade there has been considerable progress in development of more effective treatments for CLL, but current consensus is that treatment of CLL should be based upon the treatment of symptomatic disease. Specific treatment decisions based upon the detection of “high-risk” features remains a question for clinical trials, which will address the potential value of early treatment for specific groups of patients and whether all patients with CLL should receive a standard treatment or whether treatment should be modified in different risk groups.

Despite advances in treatment, there was little evidence until recently that this led to improvement in the survival of patients with indolent lymphoma, with patients continuing to have an unremitting course of relapse of disease. There appears to have been a change in the natural history of these diseases with the introduction of chemoimmunotherapy that may finally result in improvements in survival. With so many agents available for the treatment of indolent lymphomas, questions that have to be addressed include the following: is there still a role for a “watch-and-wait” approach in asymptomatic patients or should they be treated at diagnosis, what are the optimal first-line and salvage treatments, what is the role of maintenance therapy, and is there any role for stem cell transplantation in these diseases? No established treatment of choice has yet emerged, and many of these questions remain unresolved. It is highly likely that our treatment approaches will continue to evolve as the results of ongoing clinical trials are released and that improvement in outcome will result from identification of therapies that target the underlying pathophysiology of the diseases.

Although there have been no randomized trials comparing the outcome of stem cell transplantation (SCT) with standard chemotherapy for patients with chronic lymphocytic leukemia (CLL), increasingly, both autologous and allogeneic SCT approaches are being explored in this disease. Clinical trials have demonstrated that these approaches are feasible, but current data suggest that autologous transplantation is not curative and myeloablative SCT, although offering the potential for cure, is associated with high treatment-related mortality. There is a clear demonstration of a graft-versus-leukemia effect in CLL, with encouraging results seen after SCT with reduced-intensity conditioning. Because no other treatment modalities are curently capable of improving survival in this disease, the treatment of choice for younger patients with poor-risk CLL may well be SCT, but continued enrollment of appropriate patients into well-designed clinical trials is vital to compare advances in SCT with the advances occurring in chemoimmunotherapy in CLL.

Heteroclitic peptide modifications increase immunogenicity, allowing generation of cytotoxic T lymphocytes (CTLs) against weakly immunogenic tumor-associated antigens (TAAs). A critical issue is whether T cells generated against heteroclitic peptides retain the ability to recognize and kill tumor cells expressing the original weak TAAs, and whether there is a lower threshold of binding affinity of the native peptides, below which such CTLs can still kill primary tumor cells. To examine this we used a model examining the ability of native and heteroclitic immunoglobulin (Ig)–derived peptides to generate CTLs that can kill chronic lymphocytic leukemia (CLL) cells. We demonstrate that CTLs generated against heteroclitic peptides have enhanced killing of CD40-activated B cells pulsed with either heteroclitic (P < .001) or native peptide (P = .04) and primary CLL cells (P = .01). The novel finding reported here is that the rate-limiting factor appears to be the ability to generate CTLs and that once generated, CTL lysis of primary tumor cells is independent of the binding affinity of the native peptide. These findings have implications for vaccination strategies in malignancies and are currently being further examined in vivo in murine models.