Radiotherapy has been used for more than a hundred years to cure or locally control tumors. Regression of tumors outside of the irradiated field was occasionally observed and is known as the abscopal effect. However, the occurrence of systemic anti-tumor effects was deemed too rare and unpredictable to be a therapeutic goal. Recent studies suggest that immunotherapy and radiation in combination may enhance the abscopal response. Increasing numbers of cases are being reported since the routine implementation of immune checkpoint inhibitors, showing that combined radiotherapy with immunotherapy has a synergistic effect on both local and distant (i.e., unirradiated) tumors. In this review, we summarize pre-clinical and clinical reports, with a specific focus on the mechanisms behind the immunostimulatory effects of radiation and how this is enhanced by immunotherapy.

The Abscopal Effect: A Review of Pre-Clinical and Clinical Advances.

In the era of precision medicine, radiation medicine is currently focused on the precise delivery of highly conformal radiation treatments. However, the tremendous developments in targeted therapy are yet to fulfill their full promise and arguably have the potential to dramatically enhance the radiation therapeutic ratio. The increased ability to molecularly profile tumors both at diagnosis and at relapse and the co-incident progress in the field of radiogenomics could potentially pave the way for a more personalized approach to radiation treatment in contrast to the current ''one size fits all'' paradigm. Few clinical trials to date have shown an improved clinical outcome when combining targeted agents with radiation therapy, however, most have failed to show benefit, which is arguably due to limited preclinical data. Several key molecular pathways could theoretically enhance therapeutic effect of radiation when rationally targeted either by directly enhancing tumor cell kill or indirectly through the abscopal effect of radiation when combined with novel immunotherapies. The timing of combining molecular targeted therapy with radiation is also important to determine and could greatly affect the outcome depending on which pathway is being inhibited.

/pdf/clinical-and-preclinical-outcomes-of-combining-targeted-2ek74up5qx.pdf

Clinical and Preclinical Outcomes of Combining Targeted Therapy With Radiotherapy.

https://doi.org/10.1016/j.medj.2023.02.003

The abscopal effect in patients with cancer receiving immunotherapy

Triple-negative breast cancer (TNBC) is the most violent class of tumor and accounts for 20-24% of total breast carcinoma, in which frequently rare mutation occurs in high frequency. The poor prognosis, recurrence, and metastasis in the brain, heart, liver and lungs decline the lifespan of patients by about 21 months, emphasizing the need for advanced treatment. Recently, the adaptive immunity mechanism of archaea and bacteria, called clustered regularly interspaced short palindromic repeats (CRISPR) combined with nanotechnology, has been utilized as a potent gene manipulating tool with an extensive clinical application in cancer genomics due to its easeful usage and cost-effectiveness. However, CRISPR/Cas are arguably the efficient technology that can be made efficient via organic material-assisted approaches. Despite the efficacy of the CRISPR/Cas@nano complex, problems regarding successful delivery, biodegradability, and toxicity remain to render its medical implications. Therefore, this review is different in focus from past reviews by (i) detailing all possible genetic mechanisms of TNBC occurrence; (ii) available treatments and gene therapies for TNBC; (iii) overview of the delivery system and utilization of CRISPR-nano complex in TNBC, and (iv) recent advances and related toxicity of CRISPR-nano complex towards clinical trials for TNBC. 

https://doi.org/10.1016/j.mtbio.2022.100450

Nanomaterial-assisted CRISPR gene-engineering – A hallmark for triple-negative breast cancer therapeutics advancement

Radiotherapy is essential for treating unresectable or metastatic breast cancer, but radiotherapy‐induced tumor cell death generates small extracellular vesicles (sEVs) that promote tumor regrowth and metastasis following treatment. Here cationic nanosheets with a high sEVs‐binding capacity that suppress sEVs‐induced tumor regrowth and metastasis following radiotherapy is developed. Molybdenum disulfide (MoS2) monolayers are prepared by using lithium ions as intercalation agents, and are functionalized with cationic polyamidoamine (PAMAM) dendrimers. The MoS2‐PAMAM particles exhibit a corrugated sheet‐like nanostructure with a larger surface‐to‐volume ratio than spherical PAMAM‐functionalized particles, resulting in greater sEVs binding capacity. Treatment of MDA‐MB‐231 human breast cancer cells with the MoS2‐PAMAM nanosheets reduces sEVs‐induced Toll‐like receptor activation and tumor cell proliferation, migration, and invasion to a greater extent than treatment with spherical PAMAM nanoparticles. In a mouse 4T1 metastatic breast cancer model, the nanosheets exhibit greater inhibition of tumor regrowth and metastasis after radiotherapy than the spherical nanoparticles, demonstrating the potential of these sEVs‐scavenging nanosheets for improving outcomes for breast cancer radiotherapy patients. The work reveals a pivotal role of the 2D sheet‐like materials in binding sEVs, indicating the significance of nanoscale geometry in developing the next‐generation sEVs‐scavenging biomaterials.

Scavenging Tumor‐Derived Small Extracellular Vesicles by Functionalized 2D Materials to Inhibit Tumor Regrowth and Metastasis Following Radiotherapy

The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses. In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0–N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT. Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt
 . Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17–0.88) P = 0.0091. TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect. ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).

/pdf/new-clinical-and-biological-insights-from-the-international-1nr0xgwdq0.pdf

New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer

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New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer