The Seventh Annual AACR-CRI Lloyd J. Old Award in Cancer Immunology

Abstract

Established in 2013 in honor of Dr. Lloyd J. Old— the father of modern tumor immunology who served as the Cancer Research Institute s founding scientific andmedical director—the American Association for Cancer Research and Cancer Research institute (AACR-CRI) Lloyd J. Old Award in Cancer Immunology recognizes scientists whose work has significantly advanced the field of cancer immunology. On Tuesday, April 2, 2019, at the 2019 AACR annual meeting in Atlanta, the seventh annual Lloyd J. Old Award was presented to Dr. Cornelis J. M. Kees Melief. Dr. Melief is currently the chief scientific officer at ISA Pharmaceuticals and emeritus professor of tumor immunology at the Leiden University Medical Center in the Netherlands. Melief, who bonded with Lloyd Old over their passion for immunology as well as their love of classical music, is being honored for his contributions to our basic understanding and clinical applicationof vaccine-based immunotherapies, especially those against virus-induced tumors. Melief s work has been instrumental in the development of synthetic long peptide (SLP) vaccines for the treatment of cancers associated with human papillomavirus (HPV). In 1989, the Melief team reported a breakthrough in the understanding of antitumor immune responses with their demonstration of the central role that adenovirus-specific cytotoxic CD8þ T lymphocytes (CTL) play in eliminating large, vascularized, adenovirus-induced tumors in mice. Long-term immune memory persisted for months after tumor eradication. Later, Melief also discovered that CD4þ T cells help the CTLs by interacting with antigen-presenting cells (APC) via the CD40CD40L pathway. Engaging this pathway increases costimulatory activity and enhances antigen presentation by APCs, which facilitates the priming of CTLs. Blockade of the CD40-CD40L pathway mitigates this priming activity. Years later, Melief would show that local delivery of stimulatory CD40 antibodies in a timecontrolled fashion can also stimulate CTL priming and promote systemic tumor elimination while minimizing the immunerelated side effects associated with systemic administration. In 1991, Melief demonstrated that vaccines comprising synthetic Sendai virus–derived peptide and incomplete Freund s adjuvant (IFA), when administered subcutaneously, can prime virus-specific CTLs and protect mice against lethal infection. This was a proof-of-principle of the usefulness of viral peptide vaccines to stimulate CTL responses. As a next step, Melief and his colleagues created a vaccine containing HPV16-derived epitopes that protects mice against the development of HPV16þ tumors. In the mid-1990s, Melief and colleagues found that intravenous administration of certain short peptides, in this case, two adenovirus peptides fitting precisely in the antigen-presenting cleft of MHCmolecules, can actually promote immune tolerance and prevent immune rejection of adenovirus antigen–expressing tumors in mice. However, this type of tolerance can be circumvented with the use of vaccines consisting of activated dendritic cells (DC) loaded with peptide. In addition, it was revealed that vaccines combining both CD4-associated and CD8-associated epitopes provide superior protection against virus-induced lymphoma in mice. Melief s work also improved our understanding of how different vaccine constructs can influence immune stimulation in vivo. In combination with the adjuvants CpG or IFA, Melief s group showed that vaccines containing long peptides are superior to those containing short peptides in the treatment of mice with established HPV16þ tumors. Whereas long peptides induce sustained CTL activity and prolonged antigen presentation byDCs in vaccine-draining lymph nodes, short-peptide vaccines induce transient CTL responses characterized by antigen presentation in non–vaccine-draining lymph nodes by other cell types. Melief later showed that DCs process and present these long peptides, whether they were associated with class I or class II MHC presentation, much more effectively than whole proteins. Melief and his colleagues found that SLP vaccination and chemotherapy are synergistic in the elimination of HPV16þ tumors in mice. This is attributed to tumor cell apoptosis and depletionof the immunosuppressivemyeloid cells thatmakeup a larger proportion of the circulating immune cells in humans with advanced HPVþ cervical cancers. Synergy is seen even when lower doses of chemotherapy are used. Bolstered by the preclinical foundation he helped build, Melief recently began applying the SLP vaccine approach in the clinic, where the strategy first demonstrated efficacy in patients with HPV16þ high-grade vulvar intraepithelial neoplasia (VIN3), a form of premalignant disease. Clinical responses are observed in half of the patients treated, and correlate with vaccine-induced T-cell responses. Complete responses, the rate of which remained stable at 2-year follow-up, are associated with HPV clearance. Because of decreased immunogenicity, SLP vaccine monotherapy proves ineffective in patients with advanced cervical cancer. Cancer Immunol Res 2019;7:1038–9