The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase 2 study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.

• MeSH
• antigeny CD274 * antagonisté a inhibitory   metabolismus   imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• imunoterapie metody   MeSH
• inhibitory kontrolních bodů * farmakologie   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádory imunologie   radioterapie   terapie   MeSH
• retrospektivní studie MeSH
• senioři MeSH
• střeva patologie   účinky záření   MeSH
• střevní mikroflóra MeSH
• zvířata MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: While radiotherapy has long been recognized for its ability to directly ablate cancer cells through necrosis or apoptosis, radiotherapy-induced abscopal effect suggests that its impact extends beyond local tumor destruction thanks to immune response. Cellular proliferation and necrosis have been extensively studied using mathematical models that simulate tumor growth, such as Gompertz law, and the radiation effects, such as the linear-quadratic model. However, the effectiveness of radiotherapy-induced immune responses may vary among patients due to individual differences in radiation sensitivity and other factors. METHODS: We present a novel macroscopic approach designed to quantitatively analyze the intricate dynamics governing the interactions among the immune system, radiotherapy, and tumor progression. Building upon previous research demonstrating the synergistic effects of radiotherapy and immunotherapy in cancer treatment, we provide a comprehensive mathematical framework for understanding the underlying mechanisms driving these interactions. RESULTS: Our method leverages macroscopic observations and mathematical modeling to capture the overarching dynamics of this interplay, offering valuable insights for optimizing cancer treatment strategies. One shows that Gompertz law can describe therapy effects with two effective parameters. This result permits quantitative data analyses, which give useful indications for the disease progression and clinical decisions. DISCUSSION: Through validation against diverse data sets from the literature, we demonstrate the reliability and versatility of our approach in predicting the time evolution of the disease and assessing the potential efficacy of radiotherapy-immunotherapy combinations. This further supports the promising potential of the abscopal effect, suggesting that in select cases, depending on tumor size, it may confer full efficacy to radiotherapy.

• MeSH
• imunoterapie * metody   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• nádory * terapie   imunologie   radioterapie   MeSH
• radioterapie metody   MeSH
• teoretické modely MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Therapy targeting immune checkpoints represents an integral part of the treatment for patients suffering from advanced melanoma. However, the mechanisms of resistance are responsible for a lower therapeutic outcome than expected. Concerning melanoma, insufficient stimulation of the immune system by tumour neoantigens is a likely explanation. As shown previously, radiotherapy is a known option for increasing the production of tumour neoantigens and their release into the microenvironment. Consequently, neoantigens could be recognized by antigen presenting cells (APCs) and subjected to effector T lymphocytes. Enhancing the immune reaction can trigger the therapeutic response also at distant metastases, a phenomenon known as an abscopal effect (from "ab scopus", that is, away from the target). To illustrate this, we present the case of a 78-year old male treated by anti-CTLA-4/ipilimumab for metastatic melanoma. The patient received the standard four doses of ipilimumab administered every three weeks. However, the control CT scans detected disease progression in the form of axillary lymph nodes metastasis and liver metastasis two months after ipilimumab. At this stage, palliative cryotherapy of the skin metastases was initiated to alleviate the tumour burden. Surprisingly, the effect of cryotherapy was also observed in untreated metastases and deep subcutaneous metastases on the back. Moreover, we observed the disease remission of axillary lymph nodes and liver metastasis two months after the cryotherapy. The rarity of the abscopal effect suggests that even primed anti-tumour CD8+ T cells cannot overcome the tumour microenvironment's suppressive effect and execute immune clearance. However, the biological mechanism underlying this phenomenon is yet to be elucidated. The elicitation of a systemic response by cryotherapy with documented abscopal effect was rarely reported, although the immune response induction is presumably similar to a radiotherapy-induced one. The report is a combination case study and review of the abscopal effect in melanoma treated with checkpoint inhibitors.

• MeSH
• antigen prezentující buňky imunologie   MeSH
• antigeny nádorové metabolismus   MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• ipilimumab terapeutické užití   MeSH
• kryoterapie MeSH
• lidé MeSH
• melanom imunologie   sekundární   terapie   MeSH
• modely imunologické MeSH
• nádorové mikroprostředí imunologie   MeSH
• nádory kůže imunologie   patologie   terapie   MeSH
• paliativní péče MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH

• MeSH
• kombinovaná terapie MeSH
• konformní radioterapie metody   MeSH
• lidé MeSH
• nádory * farmakoterapie   radioterapie   MeSH
• protinádorové látky imunologicky aktivní terapeutické užití   MeSH
• vztah dávky záření a odpovědi MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• komentáře MeSH
• souhrny MeSH

Imunoterapie anti PD-1 protilátkami je v současné době jedním ze základních léčebných postupů u melanomu, stejně tak se radioterapie, zejména v paliativní léčbě, využívá již desítky let. Výsledky nedávných studií naznačují, že imunoterapie a radioterapie mohou působit synergisticky a v některých případech vyvolávat abskopální efekt. U našeho pacienta jsme pozorovali, při kombinaci pembrolizumabu s radioterapií uzlinových metastáz, výrazné zlepšení celkového stavu, včetně stabilizace orgánových metastáz.

Immunotherapy with anti PD-1 antibodies is one of the fundamental treatment for melanoma and radiotherapy has been used for decades, especially in palliative care. Recent studies suggest that immunotherapy and radiotherapy can act synergistically and in some cases may have an abscopal effect. In our patient, we observed, when we combined pembrolizumab with radiotherapy for nodal metastases, a significant improvement in the overal condition, including stabilization of organ metastases.

• Klíčová slova
• pembrolizumab, synergický efekt, abskopální efekt,
• MeSH
• dávka záření MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   MeSH
• imunoterapie MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• lymfatické metastázy farmakoterapie   patologie   radioterapie   terapie   MeSH
• melanom * chirurgie   farmakoterapie   patologie   radioterapie   MeSH
• metastázy nádorů diagnostické zobrazování   farmakoterapie   radioterapie   MeSH
• počítačová rentgenová tomografie MeSH
• protinádorové látky imunologicky aktivní aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• Publikační typ
• kazuistiky MeSH

Moderní imunoterapie pomocí checkpoint inhibitorů zažívá v běžné klinické praxi obrovský rozmach. V preklinické i klinické praxi je pozorována synergie imunoterapie a radioterapie. Důvodem je schopnost radioterapie aktivovat protinádorovou imunitu, a to i mimo ozářené nádorové ložisko (tzv. abskopální efekt). Aktivovaná protinádorová imunita je jednou z důležitých podmínek léčebného účinku imunitních checkpoint inhibitorů.

Modern immunotherapy using immune check-point inhibitors has experienced a huge boom in routine clinical practice. In preclinical and clinical practice, synergy of immunotherapy and radiotherapy is observed. The reason is the ability of radiotherapy to activate anti-tumor immunity, even outside the irradiated tumor (abscopal effect). Activated anti-tumor immunity is one of the important conditions for the therapeutic effect of immune check-point inhibitors.

• Klíčová slova
• checkpoint inhibitory,
• MeSH
• imunoterapie MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• nádory * imunologie   radioterapie   MeSH
• protokoly protinádorové léčby MeSH
• radioterapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Radioterapie je jedna z metod léčebného armamentaria, využívaná ve všech stadiích nádorového onemocnění. V drtivé většině je indikací radioterapie lokální ošetření nádorového ložiska. Využitím moderních technik lze zvýšit efektivitu za současného snížení nežádoucích účinků. Četné literární zdroje popisují i tzv. abskopální efekt - imunitně zprostředkovanou odpověď neozářených nádorových buněk. Kombinace s imunoterapií, tzv. checkpoint inhibitory (anti-CTLA-4, anti-PD-1 a anti-PD-LI), přináší nové možnosti v posílení komplexního protinádorového účinku za současného využití abskopálního efektu.

Radiotherapy is one of the methods of therapeutic armamentarium used in all stages of cancer. In the vast majority of cases, the indication of radiotherapy is local treatment of the tumor. The use of modern techniques can increase the effect while reducing the side effects. Numerous literature sources also describe the so-called abscopal effect - an immune-mediated response of non-irradiated tumor cells. The combination with immunotherapy, the so-called checkpoint inhibitors (anti-CTL, anti-PD-1 and anti-PD-LI), brings new possibilities in enhancing the complex tumor effect while using the abscopal effect.

• Klíčová slova
• checkpoint inhibitory,
• MeSH
• imunoterapie MeSH
• klinická studie jako téma MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• nádory * imunologie   radioterapie   MeSH
• protokoly protinádorové léčby MeSH
• radioterapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Nemalobuněčný plicní karcinom je i nadále velkým socioekonomickým problémem. Většina nádorů je zachycována v pokročilém nebo metastatickém stadiu a dostupné léčebné metody, až na malý počet pacientů se specifickými mutacemi, nejsou spojeny s uspokojivými výsledky. Základem většiny režimů je radiochemoterapie, ale přidání indukční ani udržovací cytostatické léčby žádný benefit nepřineslo. Velkým příslibem je však nyní moderní imunoterapie PD-1 a PD-L1 inhibitory. Především v kombinaci s radioterapií senzibilizující k větší účinnosti této imunoterapie by se mohla brzy stát standardem většiny léčebných doporučení. Jako výhodnější se v této souvislosti jeví hypofrakcionované ozáření limitovanými cílovými objemy než užití klasické frakcionace a větších polí. Jakou roli hraje abskopální efekt, zůstává nadále nejisté.

Non-small cell lung cancer even today is a big socioeconomic problem for beeing diagnosed in an advanced or metastatic stage in majority of tumors when our treatment methods available at that time unfortunately are not associated with satisfactory results except few patients with tumors carrying specific mutations. Radiochemotherapy remains the basic standard regimen while adding induction or maintenance cytotoxic treatment did not count for any other benefit. However, modern immunotherapy by PD-1 and PD-L1 inhibitors brings a huge hope today. Mainly it's combination with radiation therapy sensibilizing to a better immunotherapy effect could become a standard part in majority of treatment guidelines. In this context, hypofractionated radiation regimens with limited target volumes seem to be preferred to normofractionation and larger fields. The role of abscopal effect remains still uncertain.

• MeSH
• imunoterapie MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• nemalobuněčný karcinom plic * imunologie   radioterapie   MeSH
• protokoly protinádorové léčby MeSH
• radioterapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Caspase 3 (CASP3) has a key role in the execution of apoptosis, and many cancer cells are believed to disable CASP3 as a mechanism of resistance to cytotoxic therapeutics. Alongside, CASP3 regulates stress-responsive immunomodulatory pathways, including secretion of type I interferon (IFN). Here, we report that mouse mammary carcinoma TSA cells lacking Casp3 or subjected to chemical caspase inhibition were as sensitive to the cytostatic and cytotoxic effects of radiation therapy (RT) in vitro as their control counterparts, yet secreted increased levels of type I IFN. This effect originated from the accrued accumulation of irradiated cells with cytosolic DNA, likely reflecting the delayed breakdown of cells experiencing mitochondrial permeabilization in the absence of CASP3. Casp3-/- TSA cells growing in immunocompetent syngeneic mice were more sensitive to RT than their CASP3-proficient counterparts, and superior at generating bona fide abscopal responses in the presence of an immune checkpoint blocker. Finally, multiple genetic signatures of apoptotic proficiency were unexpectedly found to have robust negative (rather than positive) prognostic significance in a public cohort of breast cancer patients. However, these latter findings were not consistent with genetic signatures of defective type I IFN signaling, which were rather associated with improved prognosis. Differential gene expression analysis on patient subgroups with divergent prognosis (as stratified by independent signatures of apoptotic proficiency) identified SLC7A2 as a new biomarker with independent prognostic value in breast cancer patients. With the caveats associated with the retrospective investigation of heterogeneous, public databases, our data suggest that apoptotic caspases may influence the survival of breast cancer patients (or at least some subsets thereof) via mechanisms not necessarily related to type I IFN signaling as they identify a novel independent prognostic biomarker that awaits prospective validation.

• Publikační typ
• časopisecké články MeSH

Radiotherapy (RT) plays an important role in the management of cancer patients. RT is used in more than 50% of patients during the course of their disease in a curative or palliative setting. In the past decades it became apparent that the abscopal effect induced by RT might be dependent on the activation of immune system, and that the induction of immunogenic cancer cell death and production of danger-associated molecular patterns from dying cells play a major role in the radiotherapy-mediated anti-tumor efficacy. Therefore, the combination of RT and immunotherapy is of a particular interest that is reflected in designing clinical trials to treat patients with various malignancies. The use of cytokines as immunoadjuvants in combination with RT has been explored over the last decades as one of the immunotherapeutic combinations to enhance the clinical response to anti-cancer treatment. Here we review mainly the data on the efficacy of IFN-α, IL-2, IL-2-based immunocytokines, GM-CSF, and TNF-α used in combinations with various radiotherapeutic techniques in clinical trials. Moreover, we discuss the potential of IL-15 and its analogs and IL-12 cytokines in combination with RT based on the efficacy in preclinical mouse tumor models.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH