To accelerate the passage of discoveries from the laboratory to the clinic, several steps need to be considered in any translational drug-irradiation research program.
Developing rigorous in vitro and in vivo preclinical models that best reflect clinical radiotherapy and drug treatment approaches is of major importance. To assess the antitumor efficacy of radiotherapy, the use of ectopic xenografts are practical for tumor measurements, but do not represent the true interactions between the tumor and the organ from which it originated. Orthotopic and immunocompetent models are more complicated to implement, but they represent a more advanced step to predict the effect of radiation in patients, taking into account the immune microenvironment. Indeed, the effects of irradiation are not limited to the tumor cell, and more and more studies empha the involvement of the tumor microenvironment, mainly vascular and immune, in the overall response to irradiation. One of the direct effects of a deficient vascular microenvironment involves poorer tissue distribution of oxygen, causing hypoxia. The quantification of this hypoxia can be used to select patients towards targeted agents reducing this hypoxic radioresistance. Pre-clinical radiotherapy raises the specific question of the radiotherapy device used for these experiments. Too often, scientific articles described at best only succinctly the irradiation parameters. Preclinical irradiation can integrate the dose-volume constraints of the organs at risk to better examine the interactions between radiosensitizing drugs and radiotherapy in terms of the probability of complications on healthy tissues and facilitate the development of combination of drugs and innovative techniques radiotherapy.
Regardless of the model, new combinations should be tested according to clinically relevant regimens in terms of total dose and radiotherapy fractionation. The first starting point for translational research is the identification of a target and the selection of a drug of interest to be tested in patients. In the past, there has been a tendency to test radiation therapy in combination with systemic agents that have shown promising activity alone or in combination. This approach has unfortunately been the source of resounding failures. It is essential to have preclinical studies describing the radiotherapy-drug combination in detail, and to test different combination schemes in animals in terms of sequence (concomitant or sequential) and doses (full dose or low dose). Preclinical in vivo models also need to assess the impact of the combination on normal tissues and to encourage phase I and phase II trials testing increasing doses of systemic agents, even in the event that a medicinal product presents a satisfactory tolerance profile in monotherapy.
To promote a systematic increase in the number and quality of clinical trials that evaluate high-tech radiotherapy combined with innovative drugs, we need to increase the dialogue with the pharmaceutical industry to prioritize the study of new molecular agents in combination with radiotherapy early during the development phase of a molecule. Despite a multitude of preclinical data demonstrating the radio-sensitizing properties of several molecules, only a minority have had a significant clinical impact. This apparent failure is undoubtedly linked to a number of factors such as the long lead times required to validate the absence of long-term toxicity of irradiation, the relatively slow adoption of new methodologies by regulators, the lack of investment of the pharmaceutical industry in the development of radiotherapy/new radiosensitizing agent combination studies, ethics committees sometimes reluctant to combined radiotherapy approaches, funders and clinicians who are likely to be cautious in their approach to adopting designs that have not been rigorously evaluated. The current growing enthusiasm for combining therapies targeting immunological checkpoints with radiotherapy is based on the interest in triggering a systemic immune response, beyond the field of irradiation. Clinical developments of immunotherapy in combination with radiation therapy raise questions about the correct combination sequence, ideal dose per fraction and fractionation. The combination with irradiation of immunomodulatory drugs also raises new questions regarding lymph node volumes since irradiation of lymph nodes (including surrounding vessels) could potentially compromise leukocyte count and migration..
By improving each step of the development of a new drug, an increasingly rapid transfer will take place from the laboratory to the patients in the development of innovative strategies combining precision radiotherapy and personalized targeted drugs.