Dr. Melief delivering the AACR-CRI Lloyd J. Old Award lecture in Atlanta, GA

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 and medical 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 application of 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 CD8+ 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 CD4+ T cells “help” the CTLs by interacting with antigen-presenting cells (APC) via the CD40-CD40L 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 time-controlled fashion can also stimulate CTL priming and promote systemic tumor elimination while minimizing the immune-related 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 HPV16+ 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 MHC molecules, 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 HPV16+ tumors. Whereas long peptides induce sustained CTL activity and prolonged antigen presentation by DCs 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 HPV16+ tumors in mice. This is attributed to tumor cell apoptosis and depletion of the immunosuppressive myeloid cells that make up a larger proportion of the circulating immune cells in humans with advanced HPV+ 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 HPV16+ 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. Immunogenicity, however, can be restored via the combination of SLP vaccine and standard-of-care chemotherapy, which depletes immunosuppressive myeloid cells without impacting lymphocyte populations. The timing of the vaccine is crucial: it is given between the second and third doses of chemotherapy to coincide with the lowest numbers of circulating myeloid cells. In as-yet-unpublished results first unveiled at the 2019 AACR meeting, Melief highlighted that the SLP vaccine–chemotherapy combination showed substantial clinical benefit.

Just last year, the overall response rate and median overall survival of patients with incurable HPV16+ oropharyngeal cancer, a type of head and neck cancer, was doubled by adding an SLP vaccine to anti–PD-1 checkpoint immunotherapy, as compared with clinical responses reported on anti–PD-1 alone in the same indication. These results were published in collaboration with Dr. Glisson from MD Anderson Cancer Center (Houston, TX). Moving forward, Melief announced his company's plans to conduct a phase III trial that will evaluate the triple combination of an SLP vaccine, anti–PD-1 immunotherapy, and chemotherapy as a first-line treatment for patients with metastatic or advanced HPV16+ cancer.

Prior to receiving the Lloyd J. Old Award, Melief received the 2009 William B. Coley Award for Distinguished Research in Tumor Immunology and the 2018 European Society of Medical Oncology (ESMO) Immuno-Oncology Award. He is also a member of the Royal Netherlands Academy of Arts and Sciences. In addition to receiving multiple grants from CRI, Melief is also a member of the CRI Scientific Advisory Council and CLIP Grant Review Committee.

Arthur N. Brodsky

Cancer Research Institute, New York, NY