Analysis of the ATM–p53–p21 Pathway Function in a CLL Trial
Lin et al. Page 4191
Lin and colleagues have tested the functional integrity of the ATM–p53–p21 pathway in chronic lymphocytic leukemia (CLL) using 278 stored samples from the LRF CLL4 trial of first-line chemotherapy. They showed that blockade of the ATM–p53–p21 pathway at the level of p21 was associated with early disease progression in patients who had achieved a complete or partial response to chemotherapy. These findings implicate cell-cycle regulation as an important determinant of early relapse and support a role for ATM–p53–p21 functional analysis in identifying patients who might derive particular benefit from postinduction maintenance therapy.
Molecular Classification of Primary Malignant Melanoma
Harbst et al. Page 4026
The molecular composition of primary melanomas remains an unsolved problem. Harbst and colleagues used molecular profiling on primary melanoma tissue and identified low-grade and high-grade forms that were reproducible across independent data sets, significantly associated with known prognostic indicators and highly predictive of disease outcome. In recovering these fossilized gene expression signatures from formalin-fixed paraffin-embedded tissue, this study represents the deepest exploration of the expression space within primary melanoma to date. In short, these findings will create new avenues of clinical diagnostics and open up previously obscured vistas in melanoma biology.
IGKV3 Proteins as “Off-the-Shelf” Vaccines
Martorelli et al. Page 4080
Cancer vaccines for B-cell lymphomas targeting idiotypic proteins constitute a promising therapeutic strategy, although the individualized production of these vaccines is still complex, costly, and poorly applicable on a large scale. Martorelli and colleagues show that these limitations may be overcome by exploiting the immunogenic properties of clonal immunoglobulin light chains of the IGKV3 family, which are broadly expressed by different B-cell lymphoproliferations. The ability of IGKV3-based recombinant vaccines to elicit cross-reactive responses against molecularly related light chains provides the rationale to activate a phase I/II study aimed at assessing the safety and efficacy of these vaccines.
A Novel Anticancer Immunocytokine Based on IL-12
Pasche et al. Page 4092
Interleukin-12 (IL-12) is a proinflammatory cytokine with potent antitumor activity, but its administration to patients has resulted in severe toxicities and limited efficacy at submilligram doses. To improve the therapeutic index of IL-12, Pasche ands colleagues developed a novel IL-12–based immunocytokine format based on the F8 antibody, specific to the alternatively spliced EDA domain of fibronectin, a marker of tumor angiogenesis. After intravenous administration, this immunocytokine selectively localized on the tumor neovasculature and potently inhibited tumor growth in 3 immunocompetent syngeneic murine models of cancer. The fusion protein was also expressed as a fully human immunocytokine, paving the way for its clinical development.