Time-synchronized immune-guided SBRT partial bulky tumor irradiation targeting hypoxic segment while sparing the peritumoral immune microenvironment
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A novel unconventional SBRT-based PArtial Tumor irradiation targeting HYpoxic clonogenic cells (SBRT-PATHY) for induction of the tumoricidal bystander (BE) and abscopal effects (AE) was developed by translating our preclinical findings to a clinic in 2016. In order to further improve BE/AE response rate, SBRT-PATHY was upgraded in 2018 by the sparing of peritumoral immune microenvironment as a new OAR, defined by its own dose-constraints. Considering the anti-tumor immune response homeostatic fluctuation, which is cyclically suppressed and incited (“switched off and on”), we synchronized SBRT-PATHY with its most excitable phase, in order to overcome tumor tolerance locally and systemically. The aim of this study, therefore, was to report on the initial results of our latest innovation aimed to further improve BE/AE response rate by testing the effectiveness of the time-synchronized immune-guided SBRT-PATHY.
Materials and methods
In order to serially map the homeostatic anti-tumor immune response-fluctuations, High Sensitive C-Reactive Protein (HS-CRP), Lactate Dehydrogenase (LDH) and Lymphocyte/Monocyte Ratio (LMR) were analyzed using high-order polynomial trend analysis as surrogate of immune system response. After the biomarker data analysis detected the immune fluctuations and related idiosyncratic immune cycle periodicity, we determined the “most favourable” and “least favourable” treatment time-positions in the immune cycle. In order to evaluate the impact of an idiosyncratic immune cycle on treatment outcomes, our first consecutive four patients were treated on the “most favourable” while the remaining four on the “least favourable” day.
The median follow-up was 11.8 months. The biomarker data analysis showed periodic immune response fluctuations of regular frequency. The “right” synchronization of SBRT-PATHY with the “most favorable day” of anti-tumor immune response was accompanied with improved clinical outcomes in terms of BE/AE-response rate.
We believe the right synchronization of radiotherapy with the homeostatically oscillating immune response may improve the probability of inducing BE/AE.
Present study has been retrospectively registered on 18th of October 2019 by the ethic committee for Austrian region „Kärnten “in Klagenfurt (AUT), under study number A 37/19.
KeywordsImmune-guided timing Partial irradiation Bystander effect Abscopal effect Tumor hypoxia Immune microenvironment
Currently, some studies have described an association between the radiation-induced lymphopenia with poor oncologic outcome, indicating that radiotherapy using large volumes and multiple daily fractions can lead to immunosuppression [8, 9]. On the other side, some studies have shown potential therapeutic benefits by eventual ablation of regulatory (“suppressor”) T cells with limited (single-dose) systemic therapies [10, 11, 12] given “at the right time” in order to selectively ablate those suppressor T cells while sparing the effector T cells. Thus, suggesting that the accurate timing of limited therapy may play a major role in treatment efficacy. Following the recent reports of the anti-tumor immune response oscillating over several days [13, 14, 15, 16], we hypothesized the following: by monitoring before the treatment immune-specific biomarkers as the surrogates of homeostatically fluctuating immune response, which is cyclically suppressed and incited (“switched off and on”), it would be possible to determine a periodicity of immune response and, based on that, to synchronize SBRT-PATHY with its most excitable phase, in order to overcome tumor tolerance locally and systemically.
In order to improve the therapeutic-ratio by exploiting BE/AE an unconventional partial tumor irradiation targeting the hypoxic segment was developed in 2016 in our institute . Our preclinical findings indicated that the hypoxic in respect to normoxic tumor cells, if selectively irradiated as inductor of BE/AE, show higher potential for the generation of BE/AE . The subsequent translation of these findings to a clinic led to the introduction of a novel SBRT-based PArtial Tumor irradiation targeting HYpoxic clonogenic cells (SBRT-PATHY) showing promising BE/AE-response rates [2, 4]. Recently, the Italian group confirmed efficacy of SBRT-PATHY in their initial experience . Considering the immune-mediated nature of BE/AE and in order to further improve BE/AE response rate, SBRT-PATHY was upgraded in 2018 by the sparing of peritumoral immune microenvironment as a new OAR, defined by its own dose-constraints [4, 6]. Our concept implied that for successful therapeutic immune modulation, the entire tumor volume may not need to be irradiated but only a part of the tumor. This should initiate antigen shedding, increase effector T cell activation and lead to favorable alterations in radiation-spared peritumoral immune environment .
The objective of this study, therefore, was to report on the initial results of our latest innovation aimed to further improve BE/AE response rate by testing the effectiveness of the time-synchronized immune-guided SBRT-PATHY.
Materials and methods
Timing of SBRT-PATHY with respect to an underlying fluctuating anti-tumor immune response
Patient and disease characteristics
Number of patients (total 8):
ECOG PERFORMANCE STATUS:
PRIMARY TUMOR SITE:
TREATED BULKY TUMOR SITE:
Neck lymph node metastasis (skin melanoma)
Bone metastasis (breast)
BULKY TUMOR PATIENTS WITH DISTANT OLIGOMETASTASES:
Lung primary(1), malignant melanoma (1), Breast(1),
BULKY TUMOR PATIENTS WITH LYMPH NODE METASTASES ONLY:
UNRESCTABLE BULKY TUMOR DIAMETER: mean/range (cm)
UNRESCTABLE BULKY TUMOR VOLUME: mean/range (cm3)
TARGETED BULKY TUMOR HYPOXIC SEGMENT: mean/range (cm3)
SYSTEMIC THERAPY (exclusively before SBRT-PATHY)
SYMPTOMS related to bulky disease:
PATIENTS TREATED AT “MOST FAVOURABLE” DAY:
Lung primary: squamous(1) and adenocarcinoma(1)
Neck lymph node metastasis of malignant melanoma of the skin
Bone metastasis of breast adenocarcinoma
PATIENTS TREATED AT “LEAST FAVOURABLE” DAY:
Lung primary: squamous(2) and adenocarcinoma(2)
Idiosyncratic immune cycle periodicity
The biomarker data analysis showed immune response fluctuations (Fig. 2) which were synchronized, following similar, regular frequency. The mean immune cycle duration was 7.3 days (range: 6.5–10). The average HS-CRP and LDH concentrations were 2.92 mg/dl (range: 0.13–7.35) and 492.8 (range: 163–1080), respectively.
In addition to the partial tumor irradiation, sparing the loco-regional immune tumor microenvironment, the timing of radiotherapy in relation to the different phases of immune response could be the critical “missing link”. Recent evidences suggested that timing of therapy may influence clinical outcomes via immune modulation of the underlying immune response-suppression rather than direct tumor effects [18, 19]. In order to serially map the homeostatic immune response-fluctuations, we used Hs-CRP, LDH and LMR as surrogate of immune system interactions [15, 18, 19]. Since CRP synchronously rises and falls with initiation and termination of the immune response, we determined the start of the cycle as the “most favourable” day of the immune cycle “to release tumor antigen” by SBRT-PATHY, while the first day(s) of CRP fall as the “least favourable” (Fig. 2). This observations were accompanied with clinical outcomes suggesting significant BE/AE with the “most favorable day” approach.
The effectiveness in terms of BE/AE response rate of our novel concept could be explained by preserving the pre-existing/endogenous immune signaling in the non-irradiated tumor segment to be modulated by a sufficient threshold of cellular debris/antigen flow by SBRT-PATHY-induced cell damage. This could be seen as analogous to “radio-vaccination” event of manipulating the immunologic homeostatic balance of responsiveness and tolerance via endogenous inflammatory signals. In particular, in order to successfully modulate/disturb the homeostatic tumor immune-suppression, the immune system needs to be preserved as a real OAR.
To our knowledge, this is the first evidence of a prospectively collected time-synchronized immune-guided radiotherapy in treating unresectable bulky tumor patients. We believe the right synchronization of radiotherapy with the homeostatically oscillating immune response may improve the probability of inducing BE/AE. Larger prospective trial on time-synchronized immune-guided SBRT-PATHY is ongoing at our institute.
Authors would like to thanks to Prim. Dr. Raunik W. for the general support in performing the study.
M.A. and B.J. helped with analysis of the results and write the manuscript.
All authors read and approved the final manuscript.
Ethics approval and consent to participate
All procedures performed in present study were in accordance with the ethical standards. The informed consent was obtained for each patient before any medical act is performed. Present study has been registered by the local ethic committee for Austrian region „Kärnten “in Klagenfurt (AUT), under study number A 37/19.
Consent for publication
Tubin Slavisa M.D. reported on international patent application PCT/EP2019/052164 published as WO 2019/162050. The authors reported no other conflicts of interest.
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