The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Medical Oncology.
Aim and focus
The aim of our Experimental Cancer Immunology and Therapy program is to implement immunotherapy as treatment modality for patients with solid tumors and is focused on the exploration of key factors in host-tumor interactions that determine successes and failures in immune control of cancer.
Position in international context
The research group in Leiden belongs to the top groups in the world that successfully combines fundamental tumor immunological research and clinical trials. The clinical immunotherapy trials are guided by high quality immunomonitoring according to international standards. The group is well recognized and respected for its work in all these areas. Members of the group are/have been board members of the Dutch Cancer Society Scientific Council, the Australian Cancer Research Foundation Medical Research Advisory Committee, the International American Association for Cancer Research’s (AACR)-Cancer Immunology Working Group, Association for Immunotherapy of Cancer (CIMT) and the CIMT’s Immunoguiding Program (Founder/Chair) and the Dutch Oncolytic Viro-ImmunoTherapy consortium (OVIT). They are represented in the editorial boards of key journals dedicated to this research subject (e.g. J. Translational Medicine, Cancer Immunology Immunotherapy, Cancer Immunology Research, OncoImmunology, Journal for ImmunoTherapy of Cancer, Frontiers in Immunology and Oncology). Members of the team have been/are involved in the international scientific/program committees for international meetings of the International Papillomavirus Society, the CIMT, the AACR, PIVAC, EUROGIN and the European Society of Medical Oncology (ESMO).
Content / highlights / achievements
To achieve our aims, we perform several types of fundamental, translational and clinical studies in which we focus on Human Papilloma virus-induced cancers, Ovarian cancer, Melanoma and Pancreatic cancer.
A major focus of our group concerns the reinforcement of tumor-specific CD4+ and CD8+ T cell responses using vaccines, immune modulatory antibodies and adoptive T cell transfer. Current work is geared towards the exploration of tumor-specific antigens (neo-epitopes, TEIPP and viral oncoproteins) and studies of T cell function in an immune suppressive microenvironment, with emphasis on the manipulation of intratumoral myeloid cells. A large effort is put in comprehensive studies of mouse tumor models and patient cohorts to study the presence, type and status of systemic and local immune cells in (pre-)cancers in relation to therapy response and clinical outcome. Research lines that represent early development encompass our work on T cells expressing NK-like receptors and the regulatory role of HLA-E.
We strive to translate our pre-clinical studies to clinical trials. We co-invented and developed synthetic long peptides (SLP) as therapeutic cancer vaccines. We have tested the immunological and clinical response to several types of SLP vaccines in both animal models and in a number of phase I/II clinical trials. Based on the synergistic effects seen when several chemotherapeutic agents were tested in combination with SLP vaccination in mice, we have started to unravel the basis for these synergistic effects and started a series of clinical trials to validate these observation in patients with different types of cancer. Moreover, we have developed a method to ex-vivo obtain and expand high numbers of tumor-specific T cells as well as developed a strategy that allows their infusion into melanoma patients (ACT) under less harsh preconditioning regimens requiring only short-term hospitalization. A similar protocol is developed for ovarian cancer.
- The identification of a novel category of cancer antigens (TEIPP) that become visible to T cells on tumor cells with deficiencies in MHC class I antigen presentation.
- The demonstration that the thymic education of TEIPP-specific T cells is efficient and provides a fully functional repertoire.
- The identification of several human TEIPP targets.
- The demonstration that SLP vaccines are highly immunogenic as well as the underlying mechanisms for this.
- The completion of a series of trials in patients at different stages of disease that lead to the improved safety and immunogenicity of SLP vaccination.
- First demonstration of clinical benefit and correlates of immune protection in two clinical trials in patients with HPV16-induced high-grade lesions of the vulva vaccinated with a HPV16 E6 and E7 SLP vaccine.
- Demonstration of the different mechanisms underlying the immune stimulatory effects of non-immunogenic cell-death inducing chemotherapeutics on therapeutic cancer vaccination.
- Completion of 5 cohort studies or pilot trials to obtain information on the best timing of vaccination during standard chemotherapy and/or radiotherapy in patients with cancer of the cervix, ovaries or lung.
- Completion of a phase I/II study showing that timed SLP vaccination during chemotherapy-induced normalization of myeloid cells fosters robust T cell responses followed by a large phase 2 study suggesting clinical benefit of this approach.
- The demonstration that melanoma-specific T cells expanded from the blood via mixed tumor cell lymphocyte cultures provide clinical benefit when transfused in interferon-alpha conditioned stage IV melanoma patients (ACT).
- First demonstration of the dynamic interactions between CD4+ and CD8+ T cells reactive to mutated antigens (neo-epitopes) and melanoma cancer cells leading to immunoediting of tumors in patients treated with ACT.
- The identification of a 4-parameter tumor immune signature associated with long term survival and clinical benefit from ACT in melanoma.
- The demonstration that rather than simply depleting myeloid cells, methods that alter the intratumoral myeloid cell composition are required for optimization of immunotherapy.
- The demonstration that HLA-E expression by (pre-)malignant cells bears a negative impact on the survival of patients with strongly T-cell infiltrated tumors.
- The first demonstration that intratumoral HPV -specific type 1 polarized T-cells provides HPV16-positive oropharyngeal cancer patients with a 37-fold higher chance to respond excellently to standard therapy, across all TNM stages.
- Positive external audits of our immunomonitoring facility with respect to the compliance to the requirements and international expectations applicable for bio-analytical testing in clinical studies in 2010, 2013 and 2015, with a positive internal audit in 2014 and 2015.
- We have filed and obtained several patents on: 1) the use of long peptides as vaccines for HPV16 and for p53 as targets, 2) the method and means for the treatment of HPV induced intraepithelial neoplasias, 3) HPV epitopes targeted by T cells infiltrating cervical malignancies for use in vaccines, 4) intradermal HPV vaccination, and 5) CD94/NKG2A and/or CD94/NKG2B antibody vaccine combinations.
- In the last 8 years we have obtained over 4.3M EUR for our work on HPV, 2.5M EUR to sustain our activities within the CIMT-Immunoguiding program, 1.4M EUR for our work on TEIPP, 1.6M EUR for our work on adoptive T cell transfer, 2M EUR on immune modulatory antibodies, 1.4M EUR neoantigen-related studies, and 0.8M EUR for myeloid cell research from different charity organizations and industry partners, including Kite Pharma, Innate Pharma and ISA Pharmaceuticals (http://www.isa-pharma.com/), a spin-off company from the LUMC that valorizes our patents to develop SLP vaccines for the treatment of cancer.
Based on our published and unpublished work we have embarked on studies that address the use of oncolytic viruses in the immunotherapy of cancer, the presence and function of NK-like receptors on tumor-specific T cells, and the potential of the neoantigen landscape for exploration in therapy pipelines.
Cohesion within LUMC
The immunotherapy of cancer is one of the three major themes within the medical research profile areas Cancer Pathogenesis and Therapy (CPT) of the LUMC, as well as within the LUMC’s Female Cancer Center and the Skin Cancer & Melanoma Center. For our tumor immunological work, the production of GMP grade therapeutics and clinical trials we strongly collaborate with IHB, Head & Neck Surgery, Gynecology, Ophthalmology, Dermatology, Surgery, Pathology and the GMP-certified Interdivisional GMP Facility Leiden (IGFL). Members of our group are part of the management team of the CPT, the Flow Core Facility (FCF) and/or study coordinators of teaching modules for students of Biomedical Sciences, Biopharmaceutical Sciences and Medicine in order to educate on tumor immunology and therapy.