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Encouraging SBRT-PATHY-clinical outcomes, together with immunohistochemical and gene-expression analyses of surgically removed abscopal-tumor sites, suggested that delivery of the high-dose radiation to the partial (hypoxic) tumor volume, with optimal timing based on the homeostatic fluctuation of the immune response and sparing the peritumoral immune-environment, would significantly enhance the immune-mediated anti-tumor effects.
- immune-microenvironment,partial irradiation,SBRT
1. Introduction
With the remarkable technological developments in the treatment planning and delivery, the modern high-precision, image-guided radiotherapy becomes one of the leading treatment options in cancer management. Stereotactic body radiotherapy (SBRT) delivers an ablative radiation dose to a tumor with millimetric accuracy, exposing some portion of the surrounding healthy tissues to a mid-low radiation dose. SBRT represents the treatment of choice for limited-volume primary and metastatic lesions, especially for the patients who refuse surgery, or for whom surgery is not indicated. Based on the tumor volume and radiation dose used, for most of the treated lesions, local control rates of 80% or higher can be reached with an improvement of the overall survival, even for oligometastatic patients [1,2]. However, these clinical outcomes cannot be reproduced by the patients with high-volume tumors even with most advanced radiotherapy techniques, which is especially true for patients with unresectable bulky tumors. In most of these cases, the delivery of an ablative radiation dose to the whole tumor by means of conventional radiotherapy is limited by surrounding tissue tolerance that makes a curative treatment demanding. Bulky tumors are very challenging to treat not only because of the high volume and intimal relationship with usually infiltrated nearby organs, but also because of the presence of tumor hypoxia determining an adverse prognosis [3]. Additionally, radiotherapy of large-volumes, which is the case for bulky tumors, might potentially bring another unfavorable aspect of radiation-induced lymphopenia.
Radiotherapy has the immunomodulatory potential thereby affecting the dynamics of the immune response. The present evidence on the interaction between the radiation and immune system are controversial, showing that radiation can exert both immune-stimulatory [4,5,6] and immune-suppressive effects [7,8]. The clinical dominance of such radiation-mediated immune effects is determined by the irradiated-volume, dose-fractionation and radiotherapy technique. Clinical data show that the conventional radiotherapy predominantly generates immune-suppressive effects [9]. Furthermore, it has been shown that irradiation of larger volumes in multiple daily fractions correlates with radiation-induced lymphopenia [10,11], leading to a global immunosuppression and consequent poor oncologic outcome [12,13]. These radiation-mediated immune-suppressive effects may negatively affect the therapeutic efficacy in many tumor types [14,15]. This also results in the inhibition of immune-stimulatory effects, consequently blocking the induction of immune-mediated abscopal effects (AE).
Since the 1950s, when it was described for the first time [16], radiation-induced AE has attracted lot of interest in the radiation oncology community due to its therapeutic potential, especially in the last decade-era of immunotherapy. AE (systemic) together with radiation-induced bystander effect (BE, local), represent phenomena of non-targeted (outside the irradiated treatment field) anti-tumor effects of radiation [17]. Practically, this means induction of regression of distant-metastatic (AE) and loco-regional (BE) tumor tissues that were not directly targeted with local radiation. Although AE was a very rare clinical phenomenon in the last six decades, an increasing number of reports have been recorded after the use of SBRT in combination with immunotherapy [18]. Hypothetically, the mechanisms behind AE and BE are “immune-mediated” or “cytokines-based” [19], being cellular and soluble mediators probably both involved. AEs have been sporadically documented, especially following hypo-fractionated high-dose radiotherapy while BEs have not been reported in the clinic following the conventional whole-tumor irradiation. First experimental evidence on BEs appeared in 1990s [20]. Since then, exclusively unconventional, “spatially-fractionated” approaches like SBRT-based PArtial Tumor irradiation targeting HYpoxic tumor segment (SBRT-PATHY), GRID or LATTICE brought BEs to the clinic [21,22,23,24]. Particularly, these techniques expose only some parts of the tumor (and not total tumor) to the high-ablative radiation dose sparing the peritumoral tissue which is compatible with triggering the mechanisms responsible for BE-induction.
2. Why Timing of SBRT-PATHY May Be Important to Break Tumor Tolerance
As far back as 1913 it was hypothesized that “Roentgen Therapy” could affect the immune system and elicit “radio-vaccination” effects [45]. In 1978, Hellstrom et al. hypothesized that an effective tumor response to low dose total body irradiation, could be explained by radiation damage to normal lymphocytes rather than its direct anti-tumor effect, leading to even complete tumor regression [46,47]. One year later, original experiments by Stone et al. had shown the potential role of T cells in tumor elimination by focal radiotherapy [48]. Twice as high a dose of radiotherapy was required to exert an equivalent anti-tumor effect in T cell-deficient animals compared to an immunocompetent mouse. Then, in the late 1980s a series of experiments in mouse tumor models published by RJ North et al. had shown that single, “sub-tumoricidal” doses of either radiotherapy or chemotherapy might cause tumor elimination and prolong survival via immune modulation rather than direct tumor cytotoxicity [49]. The curative effect was reliant on the accurate timing of a single, “pulse” therapy on a specific day post-tumor implantation. Further, if the therapy was applied on days earlier or later than the optimal time, the tumor might even progress. In immune incompetent mice there was no curative effect following the “sub-tumoricidal” single doses. Thus, the timing of therapy and an intact immune system was critically needed to therapeutic success via immune modulation and not direct cytotoxic effect on the tumor.
In order to maximize the probability of therapeutic success in terms of BE/AE-induction, recently, we designed a treatment protocol for serial monitoring of immune-system activity and subsequent synchronization of SBRT-PATHY with its most reactive phase. In addition to partial tumor irradiation targeting of the hypoxic segment and sparing of PIM, SBRT-PATHY was delivered in an estimated “right time”. Importantly, the timing of treatment initiation was determined from a two-week serial monitoring schedule consisting of seven blood-tests measuring Hs-CRP, lymphocytes/monocytes ratio (LMR), and LDH, with the aim to detect the patient’s idiosyncratic cyclical immune fluctuations and periodicity. The putative radiotherapy delivery dates were projected forward into either the 3rd or 4th week following the two weeks of serial monitoring. Specifically, the radiotherapy was given in the pre-trough region on those dates [43]. The hypothesis of our group is that radiation-induced cell killing and subsequent tumor antigen release might result in generation of endogenous cytokines, leading to an effective local and systemic immune-mediated tumor elimination if PIM is radiation-spared and radiation delivered “on right time”. Further, cytokine generation might show the potential to produce endogenous therapeutic levels and thus favorably modulate the underlying local tumor-induced immune suppression in order to stimulate antitumor immunity and systemically break tumor tolerance. Our preliminary data showed cyclical immune response fluctuations of regular frequency. The “right” synchronization of SBRT-PATHY with cyclical antitumor immune activity showed promising clinical outcomes in terms of BE/AE-induction [43]. This topic is the subject of further research for our ongoing prospective trial [44].
3. Conclusions
In conclusion, adding an immune component in terms of BE/AE to radiation in tumor cell killing may improve the radiotherapy therapeutic ratio in patients that were expected to do poorly otherwise. It seems that the sparing of loco-regional immune cells at the time of an effective tumor-antigen release following the high-dose radiation of massive tumors is capable of inducing immunomodulatory effects of SBRT-PATHY, which may explain the clinical outcomes supported by immunohistochemistry- and gene expression analysis. The future of the radiation-induced immune-mediated non-targeted effects seems to be promising and beyond the conventional treatment approaches, requiring an optimization of radiotherapy in order to increase its immunogenicity. However, further controlled trials and mechanistic investigations in model systems will be required to rigorously dissect and finally confirm the potential role of “soluble abscopal signals” released by tumor microenvironment and tumor itself following partial irradiation. Several studies on SBRT-PATHY approach are ongoing in order to address the mechanisms behind the radiation-hypoxia-induced BE/AE, advantages that carbon-ions might add to this approach in terms of their inverse dose-depth profile, high-LET (linear energy transfer) and RBE (relative biologic effectiveness), as well as the role of PATHY-timing in generating BE/AE (42, 44).
This entry is adapted from the peer-reviewed paper 10.3390/cancers13010050
