Immune checkpoint inhibition (ICI) targeting the programmed death receptor 1 (PD-1) has shown promising results in the fight against cancer. Systemic anti-tumor reactions due to radiation therapy (RT) can lead to regression of non-irradiated lesions (NiLs), termed “abscopal effect” (AbE). Combination of both treatments can enhance this effect. The aim of this study was to evaluate AbEs during anti-PD-1 therapy and irradiation. We screened 168 patients receiving pembrolizumab or nivolumab at our center. Inclusion criteria were start of RT within 1 month after the first or last application of pembrolizumab (2 mg/kg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks) and at least one metastasis outside the irradiation field. We estimated the total dose during ICI for each patient using the linear quadratic (LQ) model expressed as 2 Gy equivalent dose (EQD2) using α/β of 10 Gy. Radiological images were required showing progression or no change in NiLs before and regression after completion of RT(s). Images must have been acquired at least 4 weeks after the onset of ICI or RT. The surface areas of the longest diameters of the short- and long-axes of NiLs were measured. One hundred twenty-six out of 168 (75%) patients received ICI and RT. Fifty-three percent (67/126) were treated simultaneously, and 24 of these (36%) were eligible for lesion analysis. AbE was observed in 29% (7/24). One to six lesions (mean = 3 ± 2) in each AbE patient were analyzed. Patients were diagnosed with malignant melanoma (MM) (n = 3), non-small cell lung cancer (NSCLC) (n = 3), and renal cell carcinoma (RCC) (n = 1). They were irradiated once (n = 1), twice (n = 2), or three times (n = 4) with an average total EQD2 of 120.0 ± 37.7 Gy. Eighty-two percent of RTs of AbE patients were applied with high single doses. MM patients received pembrolizumab, NSCLC, and RCC patients received nivolumab for an average duration of 45 ± 35 weeks. We demonstrate that 29% of the analyzed patients showed AbE. Strict inclusion criteria were applied to distinguish the effects of AbE from the systemic effect of ICI. Our data suggest the clinical existence of systemic effects of irradiation under ICI and could contribute to the development of a broader range of cancer treatments.

Combination concepts of radiotherapy and immune checkpoint inhibition are currently of high interest. We examined imaging findings, acute toxicity, and local control in patients with melanoma brain metastases receiving programmed death 1 (PD-1) inhibitors and/or robotic stereotactic radiosurgery (SRS). Twenty-six patients treated with SRS alone (n = 13; 20 lesions) or in combination with anti-PD-1 therapy (n = 13; 28 lesions) were analyzed. Lesion size was evaluated three and six months after SRS using a volumetric assessment based on cranial magnetic resonance imaging (cMRI) and acute toxicity after 12 weeks according to the Common Terminology Criteria for Adverse Events (CTCAE). Local control after six months was comparable (86%, SRS + anti-PD-1, and 80%, SRS). All toxicities reported were less than or equal to grade 2. One metastasis (5%) in the SRS group and six (21%) in the SRS + anti-PD-1 group increased after three months, whereas four (14%) of the six regressed during further follow-ups. This was rated as pseudoprogression (PsP). Three patients (23%) in the SRS + anti-PD-1 group showed characteristics of PsP. Treatment with SRS and anti-PD-1 antibodies can be combined safely in melanoma patients with cerebral metastases. Early volumetric progression of lesions under simultaneous treatment may be related to PsP; thus, the evaluation of combined radioimmunotherapy remains challenging and requires experienced teams.

While immune checkpoint inhibitors (ICIs) in combination with radiotherapy (RT) are widely used for patients with brain metastasis (BM), markers that predict treatment response for combined RT and ICI (RT-ICI) and their optimal dosing and sequence for the best immunogenic effects are still under investigation. The aim of this study was to evaluate prognostic factors for therapeutic outcome and to compare effects of concurrent and non-concurrent RT-ICI. We retrospectively analyzed data of 93 patients with 319 BMs of different cancer types who received PD-1 inhibitors and RT at the University Hospital Cologne between September/2014 and November/2020. Primary study endpoints were overall survival (OS), progression-free survival (PFS), and local control (LC). We included 66.7% melanoma, 22.8% lung, and 5.5% other cancer types with a mean follow-up time of 23.8 months. Median OS time was 12.19 months. LC at 6 months was 95.3% (concurrent) vs. 69.2% (non-concurrent; p = 0.008). Univariate Cox regression analysis detected following prognostic factors for OS: neutrophil-to-lymphocyte ratio NLR favoring <3 (low; HR 2.037 (1.184–3.506), p = 0.010), lactate dehydrogenase (LDH) favoring ≤ULN (HR 1.853 (1.059–3.241), p = 0.031), absence of neurological symptoms (HR 2.114 (1.285–3.478), p = 0.003), RT concept favoring SRS (HR 1.985 (1.112–3.543), p = 0.019), RT dose favoring ≥60 Gy (HR 0.519 (0.309–0.871), p = 0.013), and prior anti-CTLA4 treatment (HR 0.498 (0.271–0.914), p = 0.024). Independent prognostic factors for OS were concurrent RT-ICI application (HR 0.539 (0.299–0.971), p = 0.024) with a median OS of 17.61 vs. 6.83 months (non-concurrent), ECOG performance status favoring 0 (HR 7.756 (1.253–6.061), p = 0.012), cancer type favoring melanoma (HR 0.516 (0.288–0.926), p = 0.026), BM volume (PTV) favoring ≤3 cm³ (HR 1.947 (1.007–3.763), p = 0.048). Subgroups with the following factors showed significantly longer OS when being treated concurrently: RT dose 3 cm³ (p = 0.007), other cancer types than melanoma (p = 0.006), anti-CTLA4-naïve patients (p < 0.001), low NLR (p = 0.039), steroid intake ≤4 mg (p = 0.042). Specific immune responses, such as abscopal effects (AbEs), pseudoprogression (PsP), or immune-related adverse events (IrAEs), occurred more frequently with concurrent RT-ICI and resulted in better OS. Other toxicities, including radionecrosis, were not statistically different in both groups. The concurrent application of RT and ICI, the ECOG-PS, cancer type, and PTV had an independently prognostic impact on OS. In concurrently treated patients, treatment response (LC) was delayed and specific immune responses (AbE, PsP, IrAE) occurred more frequently with longer OS rates. Our results suggest that concurrent RT-ICI application is more beneficial than sequential treatment in patients with low pretreatment inflammatory status, more and larger BMs, and with other cancer types than melanoma.

Objective Several recent studies have identified a potential interaction between the vaginal microbiota and gynecological cancers, but little is known about the cervical microbiota and its changes during cancer treatment. Therefore, the aim of the study was to evaluate the quantitative and qualitative changes of cervical microbiota in patients undergoing concurrent chemotherapy and radiation treatment for locally advanced cervical cancer. Methods Cervical cytobrush samples of 15 cervical patients undergoing chemoradiation treatment were collected 1 day before starting external beam radiation therapy and on the day of the last fraction of brachytherapy. After DNA extraction, 16S rRNA amplicon sequencing of the V3–V4 region was performed on the MiSeq platform, followed by data processing and statistical analyses concerning the alpha and beta diversity of 16 samples (7 samples were excluded because of incomplete sample sets). Results The amount of amplicon yield after polymerase chain reaction analysis in post-radiation samples was significantly lower compared with the baseline samples (pre 31.49±24.07 ng/µl; post 1.33±1.94 ng/µl; p=0.007). A comparison of pre-treatment and post-treatment samples did not show significant differences regarding beta diversity (weighted UniFrac). There was no significant difference in alpha diversity, which is used to characterize species diversity within a particular community and takes into account both number and abundance (Shannon Diversity Index pre-treatment samples: 2.167±0.7504 (95% CI 1.54 to 2.79); post-treatment samples: 1.97±0.43 (95% CI 1.61 to 2.33); p=0.38). Interindividual differences in patients could partly explain some variation of the samples (permutational multivariate analysis of variance). Conclusion There was a strong reduction in cervical bacterial loads after chemoradiation. Neither alpha nor beta diversity varied significantly when baseline samples were compared with post-treatment samples.