Optimizing Radiation Therapy to Boost Systemic Immune Responses in Breast Cancer: A Critical Review for Breast Radiation Oncologists.
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ABSTRACT:
SUBMITTER: Ho AY
PROVIDER: S-EPMC7646202 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionPreclinical studies have demonstrated the ability of radiation therapy (RT) to augment immune response and tumor control by immune checkpoint inhibitors (ICI). However, numerous clinical trials combining RT and ICI have yielded relatively disappointing results. To improve understanding of optimal use of these therapies, we assessed systemic immune effects of prior RT in patients receiving ICI.Methods and materialsPre- and post-ICI blood samples were collected from patients enrolled in a prospective immunotherapy biospecimen protocol. Mutiplex panels of 40 cytokines and 120 autoantibodies (Ab) were analyzed. We identified differences in these parameters according to receipt, timing, and type of prior RT. We calculated P values using the Pearson product-moment correlation coefficient and false discovery rate (FDR) using the Benjamini-Hochberg Procedure.ResultsAmong 277 total patients, 69 (25%) received RT in the 6 months prior to ICI initiation. Among RT-treated patients, 23 (33%) received stereotactic RT, and 33 (48%) received curative intent RT. There was no significant difference in demographics or type of immunotherapy between patients according to prior RT exposure. Baseline complement C8 Ab and MIP-1d/CCL15 were significantly higher among patients with prior RT. For MIP-1d/CCL15, only prior stereotactic RT was associated with significant differences.ConclusionsPrior RT is associated with few changes in systemic immune parameters in patients receiving ICI. The underlying mechanisms and optimal approach to harnessing the potential synergy of RT and ICI require further prospective clinical investigation.
| S-EPMC10265517 | biostudies-literature
Project description:BACKGROUND:To better understand how radiation oncologists perceive intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT) for prostate cancer and how these perceptions may influence treatment decisions. METHODS:We conducted semi-structured interviews of radiation oncologists between January-May, 2016. We used a purposeful sampling technique to select participants across a wide range of experience, regions, and practice types. Two trained qualitative researchers used an inductive, iterative approach to code transcripts and identify themes. We then used content analysis and thematic analysis of the coded transcripts to understand radiation oncologists' attitudes and beliefs about IMRT and SBRT. RESULTS:Thematic saturation was achieved after 20 interviews. Participants were affiliated with academic (n?=?13; 65%), private (n?=?5; 25%), and mixed (n?=?2; 10%) practices and had a wide range of clinical experience (median 19?years; range 4-49?years). Analysis of interview transcripts revealed four general themes: 1) most radiation oncologists offered surgery, brachytherapy, IMRT, and active surveillance for low-risk patients; 2) there was no consensus on the comparative effectiveness of IMRT and SBRT; 3) key barriers to adopting SBRT included issues related to insurance, reimbursement, and practice inertia; and 4) despite these barriers, most participants envisioned SBRT use increasing over the next 5-10?years. CONCLUSIONS:In the absence of strong opinions about effectiveness, nonclinical factors influence the choice of radiation treatment. Despite a lack of consensus, most participants agreed SBRT may become a standard of care in the future.
| S-EPMC7449079 | biostudies-literature
Project description:Lots of controversies were found about the treatment in relation to radiation therapy (RT) for esophageal squamous cell carcinoma (ESCC). We designed a questionnaire of these controversies to do a pan-Chinese survey of radiation oncologists (ROs). For operable ESCC, 53% ROs chose surgery plus postoperative chemoradiotherapy (CRT), while 40% chose preoperative CRT plus surgery. For target volume of postoperative RT, most ROs (92%) would delineate tumor bed plus involved lymph nodes region before surgery. For definitive RT, most ROs (81%) would give patients higher RT dose to 60-65Gy. For radiation target volume, most ROs would give patients prophylactic irradiation of the bilateral superclavicular-lymph nodes region for cervical ESCC (93%), and the left gastric lymph nodes region for lower thoracic ESCC (72%). For the treatment of mediastinal lymph nodes, 72% ROs preferred elective nodal irradiation, while 28% did the involved nodal irradiation. For concurrent chemotherapy regimen, PF (5-Fu + cisplatin) and TP (cisplatin + paclitaxel) were used widely (49% and 46%, respectively). During simulation, four-dimensional computer tomography (4D CT) was not widely used (48%), even for cervical or lower thoracic ESCC (52%). For daily RT delivery, only 66% ROs would perform imaging guidance RT daily. In summary, more controversies existed in the treatment of ESCC with RT in China, including treatment strategy, radiation dose and target contour. Future goals include standardization of treatment strategy, radiation dose, and target contour, and application of 4D CT and daily imaging guidance, and pursuit of randomized trials in Chinese population.
| S-EPMC5471024 | biostudies-literature
Project description:Radiation therapy is a mainstay of treatment in early and locally advanced breast cancer but is typically reserved for palliation of symptomatic lesions in patients with metastatic breast cancer. With new advances in the field of tumor biology and immunology, the role of radiation in the metastatic setting is evolving to harness its immune-enhancing properties. Through the release of tumor antigens, tumor DNA, and cytokines into the tumor microenvironment, radiation augments the antitumoral immune response to affect both the targeted lesion and distant sites of metastatic disease. The use of immunotherapeutics to promote antitumoral immunity has resulted in improved treatment responses in patients with metastatic disease and the combination of radiation therapy and immunotherapy has become an area of intense investigation. In this article, we will review the emerging role of radiation in the treatment of metastatic disease and discuss the current state of the science and clinical trials investigating the combination of radiation and immunotherapy.
| S-EPMC5976948 | biostudies-literature
Project description:Despite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT, to overcome the stroma and maximize systemic outcomes. We bilaterally established 344SQ lung adenocarcinoma tumors in 129Sv/Ev mice. Primary and secondary tumors were irradiated with either high-dose or low-dose of XRT with systemic anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte associated protein 4 administration. Survival and tumor growth were monitored for the various groups, and secondary tumors were phenotyped by flow cytometry for immune populations. Tumor growth factor-beta (TGF-β) cytokine levels were assessed locally after low-dose XRT, and specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect. Through our preclinical and clinical studies, we observed that when tumor burden was high, there was a necessity of combining high-dose XRT to 'prime' T cells at the primary tumor site, with low-dose XRT directed to secondary (metastatic) tumors to 'modulate the stroma'. Low-dose XRT improved the antitumor outcomes of checkpoint inhibitors by favoring M1 macrophage polarization, enhancing natural killer (NK) cell infiltration, and reducing TGF-β levels. Depletion of CD4+ T cells and NK cells abrogated the observed antitumor effect. Our data extend the benefits of low-dose XRT to reprogram the tumor environment and improve the infiltration and function of effector immune cells into secondary tumors.
| S-EPMC7592253 | biostudies-literature
Project description:Endocrine therapy agents (the selective estrogen receptor (ER) modulators such as tamoxifen or the selective ER down-regulators such as ICI 182,780) are key treatment regimens for hormone receptor-positive breast cancers. While these drugs are very effective in controlling ER-positive breast cancer, many tumors that initially respond well to treatment often acquire drug resistance, which is a major clinical problem. In clinical practice, hormonal therapy agents are commonly used in combination or sequence with radiation therapy. Tamoxifen treatment and radiotherapy improve both local tumor control and patient survival. However, tamoxifen treatment may render cancer cells less responsive to radiation therapy. Only a handful of data exist on the effects of radiation on cells resistant to hormonal therapy agents. These scarce data show that cells that were resistant to tamoxifen were also resistant to radiation. Yet, the existence and mechanisms of cross-resistance to endocrine therapy and radiation therapy need to be established. Here, we for the first time examined and compared radiation responses of MCF-7 breast adenocarcinoma cells (MCF-7/S0.5) and two antiestrogen resistant cell lines derived from MCF-7/S0.5: the tamoxifen resistant MCF-7/TAMR-1 and ICI 182,780 resistant MCF-7/182R-6 cell lines. Specifically, we analyzed the radiation-induced changes in the expression of genes involved in DNA damage, apoptosis, and cell cycle regulation. We found that the tamoxifen-resistant cell line in contrast to the parental and ICI 182,780-resistant cell lines displayed a significantly less radiation-induced decrease in the expression of genes involved in DNA repair. Furthermore, we show that MCF-7/TAMR-1 and MCF-7/182R-6 cells were less susceptible to radiation-induced apoptosis as compared to the parental line. These data indicate that tamoxifen-resistant breast cancer cells have a reduced sensitivity to radiation treatment. The current study may therefore serve as a roadmap to the future analysis of the mechanisms of cross-resistance between hormonal therapy and radiation.
| S-EPMC4359324 | biostudies-literature
Project description:A better understanding of innate responses induced by vaccination is critical for designing optimal vaccines. Here, we studied the diversity and dynamics of the NK cell compartment after prime-boost immunization with the modified vaccinia virus Ankara using cynomolgus macaques as a model. Mass cytometry was used to deeply characterize blood NK cells. The NK cell subphenotype composition was modified by the prime. Certain phenotypic changes induced by the prime were maintained over time and, as a result, the NK cell composition prior to boost differed from that before prime. The key phenotypic signature that distinguished NK cells responding to the boost from those responding to the prime included stronger expression of several cytotoxic, homing, and adhesion molecules, suggesting that NK cells at recall were functionally distinct. Our data reveal potential priming or imprinting of NK cells after the first vaccine injection. This study provides novel insights into prime-boost vaccination protocols that could be used to optimize future vaccines.
2019-02-19 | E-MTAB-7697 | biostudies-arrayexpress
Project description:The results of this survey reveal current clinical practice in the handling of combined radioimmunotherapy with Immune Checkpoint Inhibitors (RT + ICI). We aim to provide a basis to open a discussion for clinical application of RT + ICI by analyzation of experts' assessment. We conducted a survey with 24 items with a focus on side effects of RT + ICI, common practice of scheduling and handling of adverse events. After pilot testing by radiation oncology experts the link to the online survey was sent to all members of the German Society of Radiation Oncology (DEGRO). In total, 51 radiation oncologists completed the questionnaire. Pulmonary toxicity under RT + ICI with ICIs was reported most frequently. Consensus was observed for bone and soft tissue RT of the limbs in favor for no interruption of ICIs. For cranial RT half of the participants do not suspend ICIs during normofractionated radiotherapy (nfRT) or stereotactic hypofractionated RT (SRT). More participants pause ICIs for central than for peripheral thoracic region. Maintenance therapy with ICIs is mostly not interrupted prior to RT. For management of RT associated pneumonitis under durvalumab the majority of 86.3% suggest corticosteroid therapy and 76.5% would postpone the next cycle of ICI therapy. The here obtained assessment and experiences by radiation oncologists reveal a large variability in practical handling of combined RT + ICI. Until scientific evidence is available a discussion for current clinical application of RT + ICI should be triggered. Interdisciplinary consensus guidelines with practical recommendations are required.
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Project description:MRI is increasingly used in radiation oncology to facilitate tumor and organ-at-risk delineation and image guidance. In this review, we address issues of MRI that are relevant for radiation oncologists when interpreting MR images offered for radiotherapy. Whether MRI is used in combination with CT or in an MRI-only workflow, it is generally necessary to ensure that MR images are acquired in treatment position, using the positioning and fixation devices that are commonly applied in radiotherapy. For target delineation, often a series of separate image sets are used with distinct image contrasts, acquired within a single exam. MR images can suffer from image distortions. While this can be avoided with dedicated scan protocols, in a diagnostic setting geometrical fidelity is less relevant and is therefore less accounted for. Since geometrical fidelity is of utmost importance in radiation oncology, it requires dedicated scan protocols. The strong magnetic field of an MRI scanner and the use of radiofrequency radiation can cause safety hazards if not properly addressed. Safety screening is crucial for every patient and every operator prior to entering the MRI room.
| S-EPMC6630156 | biostudies-literature
Project description:Radiofrequency ablation (RFA) is clinically adopted to destruct solid tumors, but is often incapable of completely ablating large tumors and those with multiple metastatic sites. Here we develop a CaCO3-assisted double emulsion method to encapsulate lipoxidase and hemin with poly(lactic-co-glycolic acid) (PLGA) to enhance RFA. We show the HLCaP nanoreactors (NRs) with pH-dependent catalytic capacity can continuously produce cytotoxic lipid radicals via the lipid peroxidation chain reaction using cancer cell debris as the fuel. Upon being fixed inside the residual tumors post RFA, HLCaP NRs exhibit a suppression effect on residual tumors in mice and rabbits by triggering ferroptosis. Moreover, treatment with HLCaP NRs post RFA can prime antitumor immunity to effectively suppress the growth of both residual and metastatic tumors, also in combination with immune checkpoint blockade. This work highlights that tumor-debris-fueled nanoreactors can benefit RFA by inhibiting tumor recurrence and preventing tumor metastasis.
| S-EPMC8280226 | biostudies-literature