Franziska Eckert · Stephan Huber
Department of Radiation Oncology, Eberhard Karls University of Tübingen, Tübingen, Germany
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Abstract
Different immunotherapy concepts developed over recent decades include immune checkpoint inhibition, vaccination, and T cell-engaging therapies, as well as effectors on the immunosuppressive tumour microenvironment. For all these immunotherapy approaches, combination studies with tumour irradiation have been performed in vivo and in the clinic. The results point towards possible opportunities for combination therapies to improve patient outcome.
© 2018 S. Karger AG, Basel
Historical Overview of Immunotherapy Development
Cancer Immunotherapy with Induced Erysipelas
Historically, one of the first systematic approaches to immunotherapy for cancer was therapy with induced erysipelas performed by William Coley [1]. Inoculation of bacteria (Streptococcus pyogenes) locally at the tumour site when followed by signs of local and systemic infection led to tumour shrinkage and in some patients to complete and lasting responses of inoperable cancers [2]. The mixture of heat-inactivated Streptococci and heat inactivated Serratia became known as “Coley’s toxin” [3].
Immunological Features in the “Hallmarks of Cancer”
After having focused on the 3 main pillars of oncology (surgery, radiotherapy, and chemotherapy) and the development of targeted therapies, the oncological field came back to acknowledging the role of the immune system and the efficacy of immunotherapy only recently. Thus, Hanahan and Weinberg [4] added 2 immunological features of enabling capacity and emerging hallmark in their updated review on tumour biology in 2011, namely “tumour promoting inflammation” and “evading immune destruction.” Compartments of the innate immune system, such as M2 polarised macrophages, especially contribute to cancer cell survival, angiogenesis, and invasion [5]. In addition, the release of reactive oxygen species by macrophages has a mutagenic effect which can facilitate genetic evolution [6]. Thus, “tumour promoting inflammation” was classified as an “enabling characteristic.” In contrast “evading immune destruction” was classified as an “emerging hallmark” due to the fact that mice deficient for certain immune compartments are prone to tumour development and tumour growth [7, 8].
Development of Ipilimumab
One of the major advances of immunotherapy for cancer was achieved after studying basic mechanisms of T cell function [9]. CTLA-4 was discovered as an inhibitory molecule on T cells in vitro [10] and in vivo [11] in 1995. Only 1 year later, the tumour suppressive effect of CTLA-4 inhibition was described in vivo. Sixteen years later, the monoclonal anti-CTLA-4 antibody ipilimumab was FDA approved for the treatment of advanced melanoma based on a phase III trial published in 2010 showing improved overall survival with a subset of patients achieving long-term survival [12].
Cancer Immunotherapy Concepts
Checkpoint Inhibition
Immune checkpoint inhibition has not been the first immunotherapeutic approach introduced in the clinic. However, the success of CTLA-4 [12] and PD-1/PD-L1 blockade [13, 14] in advanced melanoma and other cancer entities [15–17] has brought immunotherapy to the attention of the broad oncology community. Immune checkpoints are inhibitory receptors [18, 19], which physiologically function as “brakes” to prevent excessive immune responses to infection or trauma. In the cancer microenvironment, however, immune checkpoints are responsible for dampening anticancer immune responses [20, 21]. Many tumours actively express PD-L1 to escape immune destruction [22, 23]. Besides CTLA-4 and the PD-1 system, there are also other immune checkpoint inhibitors that have been developed during recent years and have entered early phase clinical trials such as LAG-3 and TIM-3 targeting antibodies [24].
Cancer Vaccines
The concept of anticancer vaccines is based on the fact that mutations in the cancer cell genome will lead to abnormal proteins and thus abnormal peptides presented on MHC-I molecules on cancer cells. When sensitised by vaccination the immune system might be able to recognise the altered epitopes and eradicate the tumours. The 2 main challenges for vaccine design are the choice of the antigen (e.g., dendritic cell-based approaches, peptides, whole attenuated tumour cells, RNA-based approaches) and the choice of the adjuvant required for the costimulatory signals to induce effective immune responses [25]. In addition, the strategies might differ for preventive approaches and the therapeutic setting. Cancer prevention by vaccine has become standard for virus-associated cancers, most prominently for cervical cancer caused by certain HPV (human papilloma virus) strains [26], but has also been discussed for high-risk populations for breast cancer and gastrointestinal malignancies [27, 28]. Therapeutic peptide cancer vaccines have been tested for minimal residual disease in prostate cancer [29] and in advanced renal cell carcinoma [30]. Sipuleucel-T, a dendritic cell-based vaccine has been FDA approved in castration-resistant prostate cancer [31, 32].
T Cell-Engaging Therapies
Targeting known tumour-specific or tumour-associated antigens is also the main rationale of chimeric antigen receptor T cells and T cell-engaging bispecific antibodies. With these approaches,