Faculty Bibliography

PURPOSE: Long peptides are efficiently presented to both CD4(+) and CD8(+) T cells after intracellular processing by antigen-presenting cells. To investigate the safety and in vivo immunogenicity of synthetic overlapping long peptides (OLP) from a human tumor self-antigen, we conducted a phase I clinical trial with OLP from cancer-testis antigen NY-ESO-1 in various adjuvant combinations. EXPERIMENTAL DESIGN: Twenty-eight patients with advanced ovarian cancer in second or third remission were enrolled sequentially in three cohorts and received at least one vaccination. Patients in Cohort 1 (n = 4) received 1.0 mg OLP, Cohort 2 (n = 13) received OLP in Montanide-ISA-51, and Cohort 3 (n = 11) received OLP + 1.4 mg Poly-ICLC in Montanide-ISA-51 on weeks 1, 4, 7, 10, and 13. Humoral and cellular responses were evaluated by standardized immunomonitoring techniques (ELISA, ELISPOT assay, intracellular cytokine staining, and tetramer staining). RESULTS: The vaccine was generally well tolerated with injection site reactions and fatigue that resolved. NY-ESO-1-specific antibody and CD8(+) T cells were undetectable after vaccination with OLP alone, but were found in 6 of 13 (46%) and 8 of 13 (62%) patients, respectively, after vaccination with OLP+Montanide, and in 10 of 11 (91%) and 10 of 11 (91%) patients, respectively, after vaccination with OLP+Montanide+Poly-ICLC. NY-ESO-1-specific CD4(+) T cells were detected in all patients with greater frequency and polyclonality when Montanide-ISA-51 was used for vaccination. Inclusion of Poly-ICLC as an adjuvant further accelerated the induction of NY-ESO-1-specific immune responses. CONCLUSIONS: The current study shows that NY-ESO-1 OLP vaccine is safe and rapidly induces consistent integrated immune responses (antibody, CD8(+) and CD4(+)) in nearly all vaccinated patients when given with appropriate adjuvants. Clin Cancer Res; 18(23); 6497-508. (c)2012 AACR.

CD30 expression is characteristic of the malignant Reed-Sternberg cell in Hodgkin lymphoma (HL) and several other lymphoid malignancies, such as anaplastic large-cell lymphoma (ALCL). Although unconjugated anti-CD30 antibodies have had minimal therapeutic activity in patients with HL as single agents, the CD30-directed antibody-drug conjugate (ADC) brentuximab vedotin has demonstrated activity that has resulted in its recent regulatory approval for the treatment of patients with relapsed HL and ALCL. Approximately 75% of patients with recurrent HL achieve objective responses, with the principal toxicity being peripheral neuropathy. Ongoing studies are evaluating treatment with this agent as part of first-line therapy, for patients with relapsed disease, and for patients with resistant disease and limited other options. Brentuximab vedotin demonstrates the therapeutic value of antibody-drug conjugation and serves as a model of how a novel, targeted approach can be employed to potentially further improve outcomes in settings where curative chemotherapeutic regimens are already available.

PURPOSE OF REVIEW: Although enormous progress has been made in treating non-Hodgkin's lymphoma (NHL), and some patients can be cured with combination immunochemotherapy, patients with relapsed and refractory lymphoma often succumb to their disease. Advances in our understanding of lymphoma biology and molecular pathogenesis are yielding new therapeutic targets. RECENT FINDINGS: This article reviews NHL biology and describes how our understanding of molecular pathogenesis is leading to the discovery of many therapeutic targets, including the cell signaling and cell cycle regulatory proteins, pro-apoptotic family members, the B-cell antigen receptor (BCR), and histone deacetylase. Recent preclinical and clinical data with inhibitors of phosphatidylinositol 3-kinase, AKT, mammalian target of rapamycin, histone deacetylase, bcl-2, and the Bruton's tyrosine kinase, a pivotal enzyme in the BCR pathway, are discussed. SUMMARY: Understanding these novel targets in the context of NHL biology will bring new therapies and allow us to develop new therapeutic platforms for the treatment of relapsed and refractory NHL, and will hopefully improve the clinical outcome for these patients

Proteasome inhibition forms the cornerstone of antimyeloma therapy. The first-in-class proteasome inhibitor, bortezomib, either alone or in combination with other chemotherapeutic agents, induces high overall response rates and response qualities in patients with clinically and molecularly defined high-risk disease. However, resistance to bortezomib and neurotoxicity associated with the treatment remain challenging issues. Carfilzomib is a novel, well tolerated, irreversible proteasome inhibitor with minimal neurotoxicity. Carfilzomib demonstrates promising activity in myeloma patients who are refractory to bortezomib and immunomodulatory agents. This review focuses on the pharmacology, safety, and efficacy of carfilzomib for the treatment of multiple myeloma in bortezomib-naive and bortezomib-exposed populations

PURPOSE OF REVIEW: Despite current advances in the therapy for newly diagnosed mantle cell lymphoma (MCL), relapsed MCL continues to have a poor prognosis. Advances in our understanding of the molecular pathogenesis of MCL are yielding many promising novel therapies. RECENT FINDINGS: This article reviews the unique biology of MCL and describes how our understanding of its cell cycle dysregulation, and impaired apoptotic pathways is yielding many potential therapeutic targets including cyclin D1 and the cell cycle regulatory proteins, inhibitors of mammalian target of rapamycin, the proteasome, and proapoptotic family members. Recent preclinical and clinical data with cdk inhibitors, histone deacetylase inhibitors, the proteasome inhibitor bortezomib, mammalian target of rapamycin inhibitors, and other experimental strategies such as immunotherapy and microRNA are discussed. SUMMARY: Understanding these targeted therapies in the context of the biology of MCL, has the potential to develop novel therapeutic platforms for the treatment of relapsed MCL, and will hopefully change the outcome for patients with this challenging clinical condition