Mitochondrial DNA drives abscopal responses to radiation that are inhibited by autophagy.

Autophagy supports both cellular and organismal homeostasis. However, whether autophagy should be inhibited or activated for cancer therapy remains unclear. Deletion of essential autophagy genes increased the sensitivity of mouse mammary carcinoma cells to radiation therapy in vitro and in vivo (in immunocompetent syngeneic hosts). Autophagy-deficient cells secreted increased amounts of type I interferon (IFN), which could be limited by CGAS or STING knockdown, mitochondrial DNA depletion or mitochondrial outer membrane permeabilization blockage via BCL2 overexpression or BAX deletion. In vivo, irradiated autophagy-incompetent mammary tumors elicited robust immunity, leading to improved control of distant nonirradiated lesions via systemic type I IFN signaling. Finally, a genetic signature of autophagy had negative prognostic value in patients with breast cancer, inversely correlating with mitochondrial abundance, type I IFN signaling and effector immunity. As clinically useful autophagy inhibitors are elusive, our findings suggest that mitochondrial outer membrane permeabilization may represent a valid target for boosting radiation therapy immunogenicity in patients with breast cancer.

Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects.

The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-γ-producing γδT cells in cancer lesions. The immune sensor, NOD2, limited CTX-induced cancer immunosurveillance and the bioactivity of these microbes. Finally, E. hirae and B. intestinihominis specific-memory Th1 cell immune responses selectively predicted longer progression-free survival in advanced lung and ovarian cancer patients treated with chemo-immunotherapy. Altogether, E. hirae and B. intestinihominis represent valuable "oncomicrobiotics" ameliorating the efficacy of the most common alkylating immunomodulatory compound.

Liver Metastasis Irradiation Can Restore Immunotherapeutic Responsiveness.

Allogeneic liver transplants tolerize the immune system, preventing organ rejection from the same donor. A recent article by Yu et al. shows that liver metastases can likewise prevent tumor rejection in immunotherapy-treated murine and human hosts. Furthermore, radiation can reprogram the liver microenvironment to restore systemic tumor rejection.

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Cellular senescence in the response of HR+ breast cancer to radiotherapy and CDK4/6 inhibitors.

BACKGROUND: Preclinical evidence from us and others demonstrates that the anticancer effects of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors can be enhanced with focal radiation therapy (RT), but only when RT is delivered prior to (rather than after) CDK4/6 inhibition. Depending on tumor model, cellular senescence (an irreversible proliferative arrest that is associated with the secretion of numerous bioactive factors) has been attributed beneficial or detrimental effects on response to treatment. As both RT and CDK4/6 inhibitors elicit cellular senescence, we hypothesized that a differential accumulation of senescent cells in the tumor microenvironment could explain such an observation, i.e., the inferiority of CDK4/6 inhibition with palbociclib (P) followed by RT (P→RT) as compared to RT followed by palbociclib (RT→P). METHODS: The impact of cellular senescence on the interaction between RT and P was assessed by harnessing female INK-ATTAC mice, which express a dimerizable form of caspase 8 (CASP8) under the promoter of cyclin dependent kinase inhibitor 2A (Cdkn2a, coding for p16Ink4), as host for endogenous mammary tumors induced by the subcutaneous implantation of medroxyprogesterone acetate (MPA, M) pellets combined with the subsequent oral administration of 7,12-dimethylbenz[a]anthracene (DMBA, D). This endogenous mouse model of HR+ mammary carcinogenesis recapitulates key immunobiological aspects of human HR+ breast cancer. Mice bearing M/D-driven tumors were allocated to RT, P or their combination in the optional presence of the CASP8 dimerizer AP20187, and monitored for tumor growth, progression-free survival and overall survival. In parallel, induction of senescence in vitro, in cultured human mammary hormone receptor (HR)+ adenocarcinoma MCF7 cells, triple negative breast carcinoma MDA-MB-231 cells and mouse HR+ mammary carcinoma TS/A cells treated with RT, P or their combination, was determined by colorimetric assessment of senescence-associated ß-galactosidase activity after 3 or 7 days of treatment. RESULTS: In vivo depletion of p16Ink4-expressing (senescent) cells ameliorated the efficacy of P→RT (but not that of RT→P) in the M/D-driven model of HR+ mammary carcinogenesis. Accordingly, P→RT induced higher levels of cellular senescence than R→TP in cultured human and mouse breast cancer cell lines. CONCLUSIONS: Pending validation in other experimental systems, these findings suggest that a program of cellular senescence in malignant cells may explain (at least partially) the inferiority of P→RT versus RT→P in preclinical models of HR+ breast cancer.

Perspectives in Immunotherapy: meeting report from Immunotherapy Bridge (Naples, November 30th-December 1st, 2022).

The discovery and development of novel treatments that harness the patient's immune system and prevent immune escape has dramatically improved outcomes for patients across cancer types. However, not all patients respond to immunotherapy, acquired resistance remains a challenge, and responses are poor in certain tumors which are considered to be immunologically cold. This has led to the need for new immunotherapy-based approaches, including adoptive cell transfer (ACT), therapeutic vaccines, and novel immune checkpoint inhibitors. These new approaches are focused on patients with an inadequate response to current treatments, with emerging evidence of improved responses in various cancers with new immunotherapy agents, often in combinations with existing agents. The use of cell therapies, drivers of immune response, and trends in immunotherapy were the focus of the Immunotherapy Bridge (November 30th-December 1st, 2022), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer.

Randomized phase II trial of MRI-guided salvage radiotherapy for prostate cancer in 4 weeks versus 2 weeks (SHORTER).

BACKGROUND: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens. It remains unclear whether this can be done safely and whether MRgRT may help mitigate potential toxicity. SHORTER (NCT04422132) is a phase II randomized trial prospectively evaluating whether salvage MRgRT delivered in 5 fractions versus 20 fractions is non-inferior with respect to gastrointestinal (GI) and genitourinary (GU) toxicities at 2-years post-treatment. METHODS: A total of 136 patients will be randomized in a 1:1 ratio to salvage MRgRT in 5 fractions or 20 fractions using permuted block randomization. Patients will be stratified according to baseline Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domain scores as well as nodal treatment and androgen deprivation therapy (ADT). Patients undergoing 5 fractions will receive a total of 32.5 Gy over 2 weeks and patients undergoing 20 fractions will receive a total of 55 Gy over 4 weeks, with or without nodal coverage (25.5 Gy over 2 weeks and 42 Gy over 4 weeks) and ADT as per the investigator's discretion. The co-primary endpoints are change scores in the bowel and the urinary domains of the EPIC. The change scores will reflect the 2-year score minus the pre-treatment (baseline) score. The secondary endpoints include safety endpoints, including change in GI and GU symptoms at 3, 6, 12 and 60 months from completion of treatment, and efficacy endpoints, including time to progression, prostate cancer specific survival and overall survival. DISCUSSION: The SHORTER trial is the first randomized phase II trial comparing toxicity of ultra-hypofractionated and hypofractionated MRgRT in the salvage setting. The primary hypothesis is that salvage MRgRT delivered in 5 fractions will not significantly increase GI and GU toxicities when compared to salvage MRgRT delivered in 20 fractions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04422132. Date of registration: June 9, 2020.

Benefit of adjuvant chemotherapy in node-negative T1a versus T1b and T1c triple-negative breast cancer.

PURPOSE: National comprehensive cancer network guidelines recommend delivery of adjuvant chemotherapy in node-negative triple-negative breast cancer (TNBC) if the tumor is > 1 cm and consideration of adjuvant chemotherapy for T1b but not T1a disease. These recommendations are based upon sparse data on the role of adjuvant chemotherapy in T1a and T1b node-negative TNBC. Our objective was to clarify the benefits of chemotherapy for patients with T1N0 TNBC, stratified by tumor size. METHODS: We performed a retrospective analysis of survival outcomes of TNBC patients at two academic institutions in the United States from 1999 to 2018. Primary tumor size, histology, and nodal status were based upon surgical pathology. The Kaplan-Meier plot and 5-year unadjusted survival probability were evaluated. RESULTS: Among 282 T1N0 TNBC cases, the status of adjuvant chemotherapy was known for 258. Mean follow-up was 5.3 years. Adjuvant chemotherapy was delivered to 30.5% of T1a, 64.7% T1b, and 83.9% T1c (p < 0.0001). On multivariable analysis, factors associated with delivery of adjuvant chemotherapy were tumor size and grade 3 disease. Improved overall survival was associated with use of chemotherapy in patients with T1c disease (93.2% vs. 75.2% p = 0.008) but not T1a (100% vs. 100% p = 0.3778) or T1b (100% vs. 95.8% p = 0.2362) disease. CONCLUSION: Our data support current guidelines indicating benefit from adjuvant chemotherapy in node-negative TNBC associated with T1c tumors but excellent outcomes were observed in the cases of T1a and T1b disease, regardless of whether adjuvant chemotherapy was delivered.

Natural history of lower urinary tract symptoms among men undergoing stereotactic body radiation therapy for prostate cancer with and without a Rectal Hydrogel Spacer.

PURPOSE: Stereotactic body radiation therapy (SBRT) is increasingly used for prostate cancer, but has morbidity as both the bladder and rectum are radiated during treatment. Our goal was to document and compare lower urinary tract symptoms (LUTS) among men who underwent SBRT with and without SpaceOAR hydrogel (Augmenix, Inc., Bedford, MA). METHODS: We performed a retrospective analysis of 87 men (50 SpaceOAR and 37 non-SpaceOAR) who underwent SBRT. Primary outcomes were patient reported symptoms during radiation therapy, pharmacotherapy usage, and urologic and bowel survey scores up to 6-months post-SBRT. RESULTS: 78% of men were on α-inhibitors at the end of SBRT, an increase from 27.6% baseline usage (p < 0.001). Post-SBRT urinary frequency was more common in the non-SpaceOAR group versus the SpaceOAR group (68% versus 38%, p = 0.006), as was nocturia (35% vs. 8%, p = 0.002). Acute gastrointestinal symptoms did not differ. 58.8% of men were on α-inhibitors at 6-months of follow-up post-SBRT, an increase from 27.6% baseline usage (p < 0.001). Importantly, there was a difference of α-inhibitor use between non-SpaceOAR and SpaceOAR groups at the end of SBRT and at 1.5-, 3-, and 6-months follow up (86% vs. 53% [p = 0.002], 83% vs. 53% [p = 0.005], 72% vs. 49% [p = 0.038], respectively). CONCLUSION: LUTS after SBRT remains a significant problem for men undergoing treatment for prostate cancer. LUTS affects men during and up to 6-months following SBRT. Owing to these increased LUTS, preemptive minimally invasive solutions and their mechanisms of protection, including the SpaceOAR, should be further investigated.

Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial.

BACKGROUND: Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab. METHODS: We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual. FINDINGS: Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2-79·6]; p<0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported. INTERPRETATION: Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial. FUNDING: AstraZeneca.

Phase I Trial of Cemiplimab, Radiotherapy, Cyclophosphamide, and Granulocyte Macrophage Colony-Stimulating Factor in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma.

LESSONS LEARNED: Cemiplimab in combination with radiation therapy, cyclophosphamide, and granulocyte macrophage colony-stimulating factor did not demonstrate efficacy above what can be achieved with other PD-1 inhibitor monotherapies in patients with refractory and metastatic head and neck squamous cell carcinoma. The safety profile of cemiplimab combination therapy was consistent with previously reported safety profiles of cemiplimab monotherapy. No new safety signal was observed. BACKGROUND: Refractory and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) generally does not respond to PD-1 inhibitor monotherapy. Cemiplimab is a human anti-PD-1 monoclonal antibody. An expansion cohort enrolled patients with R/M HNSCC in a phase I study combining cemiplimab plus radiation therapy (RT), cyclophosphamide, and granulocyte macrophage colony-stimulating factor (GM-CSF). METHODS: Patients with R/M HNSCC refractory to at least first-line therapy and for whom palliative RT is clinically indicated received cemiplimab plus RT, cyclophosphamide, and GM-CSF. The co-primary objectives were the safety, tolerability, and efficacy of cemiplimab plus RT, cyclophosphamide, and GM-CSF in 15 patients with R/M HNSCC. RESULTS: Fifteen patients were enrolled. Patients discontinued treatment due to progression of disease. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (40.0%), constipation (26.7%), and asthenia, dyspnea, maculo-papular rash, and pneumonia (each 20%). The only grade ≥3 TEAE that occurred in two patients was pneumonia (13.3%). By investigator assessment, there was one partial response (6.7%); disease control rate was 40.0% (95% confidence interval [CI], 16.3-67.7; five patients with stable disease); seven patients had progressive disease, and two were not evaluable. Median progression-free survival by investigator assessment was 1.8 months (95% CI, 1.7-4.7). CONCLUSION: The regimen demonstrated tolerability but not efficacy above that which can be achieved with anti-PD-1 inhibitor monotherapy for R/M HNSCC.

Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge" (December 4th-5th, 2019, Naples, Italy).

Over the last few years, numerous clinical trials and real-world experience have provided a large amount of evidence demonstrating the potential for long-term survival with immunotherapy agents across various malignancies, beginning with melanoma and extending to other tumours. The clinical success of immune checkpoint blockade has encouraged increasing development of other immunotherapies. It has been estimated that there are over 3000 immuno-oncology trials ongoing, targeting hundreds of disease and immune pathways. Evolving topics on cancer immunotherapy, including the state of the art of immunotherapy across various malignancies, were the focus of discussions at the Immunotherapy Bridge meeting (4-5 December, 2019, Naples, Italy), and are summarised in this report.

Perspectives in immunotherapy: meeting report from the immunotherapy bridge (December 2nd-3rd, 2020, Italy).

Improved understanding of tumor immunology has enabled the development of therapies that harness the immune system and prevent immune escape. Numerous clinical trials and real-world experience has provided evidence of the potential for long-term survival with immunotherapy in various types of malignancy. Recurring observations with immuno-oncology agents include their potential for clinical application across a broad patient population with different tumor types, conventional and unconventional response patterns, durable responses, and immune-related adverse events. Despite the substantial achievements to date, a significant proportion of patients still fail to benefit from current immunotherapy options, and ongoing research is focused on transforming non-responders to responders through the development of novel treatments, new strategies to combination therapy, adjuvant and neoadjuvant approaches, and the identification of biomarkers of response. These topics were the focus of the virtual Immunotherapy Bridge (December 2nd-3rd, 2020), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer and are summarised in this report.

Dual Transforming Growth Factor-ß and Programmed Death-1 Blockade: A Strategy for Immune-Excluded Tumors?

Tumors that elude infiltration by CD8+ T lymphocytes are particularly resistant to multiple forms of treatment, including immune checkpoint blockade. Stromal transforming growth factor (TGF)-ß appears to play a key role in this process, potentially constituting a target for novel combinatorial regimens tackling immune-excluded neoplasms.

Immunological Mechanisms Responsible for Radiation-Induced Abscopal Effect.

Radiotherapy has been used for more than a hundred years as a local tumor treatment. The occurrence of systemic antitumor effects manifesting as regression of tumors outside of the irradiated field (abscopal effect) was occasionally observed but deemed too rare and unpredictable to be a therapeutic goal. This has changed with the advent of immunotherapy. Remarkable systemic effects have been observed in patients receiving radiotherapy to control tumors that were progressing during immune checkpoint blockade, stimulating interest in using radiation to overcome primary and acquired cancer resistance to immunotherapy. Here, we review the immunological mechanisms that are responsible for the ability of focal radiation to promote antitumor T cell responses that mediate tumor rejection and, in some cases, result in systemic effects.

Deep learning-based synthetic CT generation for MR-only radiotherapy of prostate cancer patients with 0.35T MRI linear accelerator.

PURPOSE: To develop a deep learning model to generate synthetic CT for MR-only radiotherapy of prostate cancer patients treated with 0.35 T MRI linear accelerator. MATERIALS AND METHODS: A U-NET convolutional neural network was developed to translate 0.35 T TRUFI MRI into electron density map using a novel cost function equalizing the contribution of various tissue types including fat, muscle, bone, and background air in training. The impact of training time, dataset size, image standardization, and data augmentation approaches was also quantified. Mean absolute error (MAE) between synthetic and planning CTs was calculated to measure the goodness of the model. RESULTS: With 20 patients in training, our U-NET model has the potential to generate synthetic CT with a MAE of about 29.68 ± 4.41, 16.34 ± 2.67, 23.36 ± 2.85, and 105.90 ± 22.80 HU over the entire body, fat, muscle, and bone tissues, respectively. As expected, we found that the number of patients used for training and MAE are nonlinearly correlated. Data augmentation and our proposed loss function were effective to improve MAE by ~9% and ~18% in bony voxels, respectively. Increasing the training time and image standardization did not improve the accuracy of the model. CONCLUSION: A U-NET model has been developed and tested numerically to generate synthetic CT from 0.35T TRUFI MRI for MR-only radiotherapy of prostate cancer patients. Dosimetric evaluation using a large and independent dataset warrants the validity of the proposed model and the actual number of patients needed for the safe usage of the model in routine clinical workflow.

Quantifying the impact of SpaceOAR hydrogel on inter-fractional rectal and bladder dose during 0.35 T MR-guided prostate adaptive radiotherapy.

PURPOSE: To investigate the impact of rectal spacing on inter-fractional rectal and bladder dose and the need for adaptive planning in prostate cancer patients undergoing SBRT with a 0.35 T MRI-Linac. MATERIALS AND METHODS: We evaluated and compared SBRT plans from prostate cancer patients with and without rectal spacer who underwent treatment on a 0.35 T MRI-Linac. Each group consisted of 10 randomly selected patients that received prostate SBRT to a total dose of 36.25 Gy in five fractions. Dosimetric differences in planned and delivered rectal and bladder dose and the number of fractions violating OAR constraints were quantified. We also assessed whether adaptive planning was needed to meet constraints for each fraction. RESULTS: On average, rectal spacing reduced the maximum dose delivered to the rectum by more than 8 Gy (p < 0.001). We also found that D3cc received by the rectum could be 12 Gy higher in patients who did not have rectal spacer (p < 9E-7). In addition, the results show that a rectal spacer can reduce the maximum dose and D15cc to the bladder wall by more than 1 (p < 0.004) and 8 (p < 0.009) Gy, respectively. Our study also shows that using a rectal spacer could reduce the necessity for adaptive planning. The incidence of dose constraint violation was observed in almost 91% of the fractions in patients without the rectal spacer and 52% in patients with implanted spacer. CONCLUSION: Inter-fractional changes in rectal and bladder dose were quantified in patients who underwent SBRT with/without rectal SpaceOAR hydrogel. Rectal spacer does not eliminate the need for adaptive planning but reduces its necessity.

PD-1 blockade in recurrent or metastatic cervical cancer: Data from cemiplimab phase I expansion cohorts and characterization of PD-L1 expression in cervical cancer.

OBJECTIVES: To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression. METHODS: In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA). RESULTS: Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens (N = 155), PD-L1 protein expression in tumor and immune cells was negative (<1%) more commonly in adenocarcinoma than in squamous tumors. PD-L1 mRNA levels were lower in adenocarcinoma than squamous cell tumors (1.2 vs 5.0 mean transcripts per million, respectively) in TCGA. CONCLUSIONS: Cemiplimab has activity in cervical squamous cell carcinoma. The phase I results, combined with results from other anti-PD-1 trials in cervical cancer and our biomarker analyses have informed the design of the ongoing phase III trial, with the primary overall survival hierarchical analyses being done first in patients with squamous histology.

Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers.

Over the past few years, multiple immune checkpoint blockers (ICBs) have achieved unprecedented clinical success and have been approved by regulatory agencies for the treatment of an increasing number of malignancies. However, only a limited fraction of patients responds to ICBs employed as a standalone intervention, calling for the development of combinatorial regimens. Radiation therapy (RT) stands out as a very promising candidate for this purpose. Indeed, RT mediates antineoplastic effects not only by cytotoxic and cytostatic mechanisms, but also by modulating immunological functions, both locally (within the irradiated field) and systemically. As combinatorial regimens involving RT and ICBs are being developed and clinically tested at an accelerating pace, it is paramount to identify biomarkers that reliably predict the likelihood of individual patients to respond. Here, we discuss emerging biomarkers that may potentially predict the response of cancer patients to RT plus ICBs.