MVA-TRICOM vaccine strategy makes CLL cells an attractive T-cell target

Comment on Palena et al, page 3515

In this issue of Blood, the paper by Palena and colleagues extends potential strategies for vaccine development in CLL.

To date, vaccine strategies in CLL have been limited. This is due partly to CLL patients having an impaired immune system that in part relates to CLL cells not expressing many of the necessary costimulatory cell surface antigens required for effective T-cell recognition and activation. In the absence of such cell surface antigens, CLL cells are able to actively proliferate and remain untouched by native, anergic, autologous T cells of patients with this disease. Palena and colleagues in this issue of Blood have provided an alternative strategy to increase expression of 3 essential costimulatory molecules (CD80, lymphocyte function-associated antigen 3 [LFA-3], and intercellular adhesion molecule 1 [ICAM-1]) in primary CLL cells. Specifically, the authors examined the ability of 3 types of highly attenuated, nonreplicating engineered pox virus constructs to infect and subsequently express the 3 costimulatory molecules CD80, LFA3, and ICAM1 in primary CLL cells. In these studies, the modified vaccinia virus strain Ankara (MVA)–triad of costimulatory molecules (TRICOM) highly attenuated vaccinia virus was best able to increase both the proportion of cells expressing and antigen density of these specific antigens. Both allogeneic T cells from healthy donors and autologous T cells from patients with CLL were activated as evidenced by proliferation and cytokine release when exposed to MVA-TRICOM–infected cells. The authors then carefully demonstrate the specificity of expression of costimulatory molecules in this process by blocking studies with antibodies directed at CD80, LFA-3, and ICAM1. Cytotoxic T-cell clones derived from these studies were also able to mediate cytotoxicity toward CLL cells not infected by MVA-TRICOM.

The significance of these in vitro studies using primary CLL cells is substantial for future clinical development of vaccine strategies for this disease. A construct similar to MVA TRICOM described in this paper has been tested in immunocompromised HIV-infected patients without significant consequence. Unlike some vaccine therapies where the T-cell–specific target is known, this therapeutic approach depends upon unrecognized tumor cell antigens. Nonetheless, this paper demonstrates several ex vivo assays that can be used to follow T-cell response to native CLL cells not infected with this virus. Thus, the authors have provided preclinical evidence that this strategy might have therapeutic value in CLL and pharmacodynamic assays that could potentially be used to follow the effect of therapy in vivo.

All of the preclinical data presented by Palena and colleagues provide justification for consideration of clinical trials with this reagent. One major question that remains is the optimal clinical design of introducing MVA-TRICOM into CLL patients. Vaccine strategies generally work most effectively in the setting of minimal residual disease, which would likely necessitate treatment with CLL therapy prior to administering MVA-TRICOM. Unfortunately, CLL therapies such as fludarabine and alemtuzumab are immunosuppressive and could impact the MVA-TRICOM vaccine's success. Assessment of autologous T-cell response to MVA-TRICOM–infected CLL cells derived from patients treated with fludarabine would be an additional preclinical step to pursue. Additionally, the authors have offered that the MVA-TRICOM vaccine could occur via (1) ex vivo infection of CLL cells with the modified vaccinia virus TRICOM followed by infusion of these cells into the patient immediately after this or (2) direct administration to the patient as a vaccine. Identifying which of these schedules is optimal through preclinical animal models of CLL or as part of early clinical trials would be ideal. Palena and colleagues' data with the MVA-TRICOM vaccine clearly provide justification to pursue these additional studies. ▪