Radiotherapy combination opportunities leveraging immunity for the next oncology practice.

As well as its local effects, radiotherapy leads to the delayed regression of distant non-irradiated lesions. These abscopal effects are most likely mediated by the innate immune system. Patient 1, a 74-year-old male, had concomitant left supraclavicular lymph node metastases and multiple lung metastases 2 years after complete resection of pathological stage IIA (T1bN1M0) lung adenocarcinoma. He received radiation therapy (RT) of 58 Gy for the supraclavicular lymph node metastases and then innate immunotherapy using the cell wall skeleton of Mycobacterium bovis bacillus Calmette–Guerin (BCG-CWS). Three months after the RT and 2 months after the immunotherapy, all lung metastases disappeared on computed tomography scans. Patient 2, a 40-year-old female, underwent stereotactic body RT (SBRT) for metastasis from a deep-seated urothelial carcinoma in the right upper lobe of the lung. Twenty-one months after the SBRT, we started administration of BCG-CWS to two new lesions that had appeared in the left lung. As a result, after 3 months, the lesions completely disappeared. Complete response was maintained for more than 1 year in both patients. We believe that an optimal combination of RT and immunotherapy will elicit abscopal effects that can be employed to attain a systematically achievable, rather than anecdotal, therapeutic goal.

Emerging studies show that radiation therapy produces an important out of field (distant) effect known as the ‘‘abscopal effect” in nonirradiated tumor sites. The objective of this study was to provide an overview of the current state of knowledge and clinical experience of radiation therapy producing abscopal effects in the management of different types of malignant diseases. Peer-reviewed published clinical evidence on the abscopal effect of radiation therapy was collected using electronic databases such as Medline via PubMed and Google Scholar. The reference lists were searched in the publications that we obtained in an attempt to find additional relevant publications. Non-indexed peer-reviewed journals were manually searched and relevant information was extracted. The search was restricted to English language articles. The clinical data on the abscopal effect of radiation therapy were reviewed and the outcomes have been summarized. Currently, only clinical case reports and anecdotes have slowly converted into solid clinical data and interest is building in the field of radiation therapy, specifically on how local radiation can produce the abscopal effects for the management of different types of malignant tumors. Extensive clinical evidence suggests that the radiation therapy induced abscopal antitumor effects are mediated by immune cells such as the T-lymphocytes. This forms a basis for using radiation therapy in combination with immunotherapy to augment the abscopal response rates in cancer patients. Current evidence demonstrates that radiation therapy induces abscopal responses across many tumor types. Together, the clinical outcomes from published reports suggest that localized radiation therapy is capable of inducing abscopal effects in a wide variety of malignant tumors. With the advent of novel immunotherapies, the potential for immune activation by radiation defines a novel role for radiation therapy in the treatment of systemic disease. A clinical consideration of the abscopal effects produced by radiation therapy could lead to a revolutionary change in the current management of patients including radiation treatment strategies and immunotherapies for various malignant tumors.

Cytogenetics, Not Just Previous Therapy, Determines the Course of Therapy-Related Myeloid Neoplasms

BackgroundThe abscopal effect is a rare phenomenon whereby local radiation induces a proposed immune-mediated anti-tumor effect at distant sites. Given the growing use of immunotherapies and systemic immune checkpoint inhibitors in neuro-oncologic practice, we aimed to review prior studies pertaining to this phenomenon in the context of tumor shrinkage both within the central nervous system as well as distant disease sites.MethodsA systematic review in accordance with the PRISMA guidelines was conducted to identify all studies which assessed the abscopal effect in patients with treated metastatic cancer to the brain and/or spine. Articles were included if they reported the abscopal effect in patients (case studies) or if the abscopal effect was explicitly analyzed in case series with cohorts of patients with metastatic brain or spine tumors. Laboratory investigations and clinical trials investigating new therapies were excluded.ResultsTwenty reports met inclusion criteria [16 case reports, 4 case series (n = 160), total n = 174]. Case reports of the abscopal effect were in relation to the following cancers: melanoma (6 patients), breast cancer (3), lung adenocarcinoma (2), non-small-cell lung cancer (2), hepatocellular carcinoma (1), and renal cell carcinoma (1). Eleven patients had irradiation to the brain and 2 to the spine. Patients undergoing whole brain radiotherapy (6) had an average dose of 33.6 Gy over 8–15 fractions, and those undergoing stereotactic radiosurgery (5) had an average dose of 21.5 Gy over 1–5 fractions. One patient had radiation to the body and an intracranial abscopal effect was observed. Most common sites of extracranial tumor reduction were lung and lymph nodes. Ten case studies (57%) showed complete resolution of extra-CNS tumor burden. Median progression-free survival was 13 months following radiation. Four papers investigated incidence of abscopal effects in patients with metastatic melanoma to the brain who received immune checkpoint inhibitor therapy (n = 160); two papers found an abscopal effect in 35% and 52% of patients (n = 16, 21 respectively), and two papers found no evidence of abscopal effects (n = 61, 62).ConclusionsAbscopal effects can occur following radiotherapy in patients with brain or spine metastases and is thought to be a result of increased anti-tumor immunity. The potential for immune checkpoint inhibitor therapy to be used in combination with radiotherapy to induce an abscopal effect is an area of active investigation.

Half of all cancer patients in Europe should receive radiotherapy (RT) during the treatment of their disease. But there is a remaining gap in RT provision, leading to suboptimal access. Additionally, healthcare budgets are tight, and economic evaluations are key to support decision making. The HERO project (Health Economics in Radiation Oncology) is developing a knowledge base for health economic evaluation of RT at the European level. It aims to provide solid data to engage with decision makers; it empowers the RT community to advocate for better resource planning and ultimately better care for patients, closing the gap in RT access. The project assessed the availability of RT in Europe, in terms of equipment, staffing and guidelines. Then, it investigated the need for RT in Europe. Applying available EU data to the CCORE group (Collaboration for Cancer Outcomes Research and Evaluation) decision trees of evidence-based indications, the RT optimal utilization proportion, existing gap and growing needs have been calculated. Finally, knowing the cost of treatment is needed for budget planning and reimbursement settings, HERO developed a cost accounting model, applying a time-driven activity-based costing (TD-ABC) methodology. The model gives insight on the national cost of RT: per treatment, on average and for various tumor types and techniques, on the resources required based on national patterns of care. Regarding availability of human and capital resources, there are big discrepancies in Europe, with sixfold variations across European countries for some of the resources. Looking at the need, while on average 51% of all cancer patients should receive RT, we miss out 30% of these. The need is further expected to increase with an average of 16% by 2025. Lastly, the HERO costing model is accessible online. Preliminary results are available for a fictitious country (Europalia), whose RT scenario is based on standard European practices: to serve a hypothetical cancer patient cohort of 100,000, the model computes an annual RT budget of 173,192,960€, an average RT treatment cost of 3518€ and, for common cancer types, an average breast and prostate treatment cost of respectively 3785 and 6092€. Currently, the model is used in Belgium, to help defining resource recommendations, and other countries are setting up task forces for the implementation of the tool nationally. HERO allows to advocate for RT and negotiate with decision makers, who need data on availability, needs and costs, when planning RT resources within their country. In addition, knowledge of the RT cost will promote and further ease cost-effectiveness analyses as well as the development of value-based health care oncology programs. Overall, the HERO project creates a movement of awareness within the cancer community, encourages national RT data collection and supports the promotion of optimal access to care with the ultimate aim of better outcome for the cancer patient.

e14610 Background: Immune checkpoint inhibitors represent an important advance in cancer therapeutics. However, most cancer patients do not respond or become resistant to this form of immune therapy. Methods: We evaluated the ability of Ad-p53 to reverse immune checkpoint inhibitor resistance and induce abscopal effects in the immune therapy resistant murine B16F10 melanoma tumor model. To mimic clinical conditions of checkpoint inhibitor resistance, animals with established tumors were treated with anti-PD-1 before initiating Ad-p53 intra-tumoral therapy. Results: Anti-PD-1 had minimal therapeutic efficacy compared to control treatment. A statistical analysis of variance (ANOVA) comparison of tumor volumes revealed that the combined effect of Ad-p53 and anti-PD-1 treatment was synergistic and superior to either therapy alone (p = 0.0001). Surprisingly, there was a statistically significant abscopal effect with decreased growth of contralateral tumors not injected with Ad -p53. The Ad- p53 alone (p = 0.046) and Ad- p53 + anti-PD-1 (p = 0.0243) treatment groups both demonstrated a statistically significant decreased abscopal tumor growth compared to treatment with anti-PD-1 alone. Combined Ad- p53 and anti-PD-1 therapy demonstrated a statistically significant increase in survival compared to Ad- p53 therapy alone (p = 0.0167) and anti-PD-1 therapy alone (p < 0.001) by the log rank test. We have initiated a Phase 1 clinical trial of Ad-p53 intra-hepatic arterial therapy in combination with capecitabine for patients with solid tumor liver metastases. In the first cohort of patients at a dose of 2 x 1012viral particles, treatment has been well tolerated with transient fever, chills and rigors. In one patient, decreased SUV uptake on PET scans of distant lymph node metastases suggested possible abscopal effects. Conclusions: These results suggest that Ad-p53 tumor suppressor immune gene therapy may reverse immune checkpoint inhibitor resistance and induce abscopal effects supporting the planned clinical evaluation of combined Ad-p53 and anti-PD-1 therapy in patients resistant to immune checkpoint inhibitor therapy. Clinical trial information: NCT02842125.

Background: The term “abscopal effect” was defined in 1953. In oncology the term is used to describe systemic antitumor effects triggered by local irradiation (nontarget effect). Although the mechanism of the abscopal effect is not completely understood yet, it has been demonstrated that in situ tumor vaccination, and the resulting antitumor immune response, is one of the key factors. Summary: The development of immune therapies has recently led to concepts combining local radiotherapy and immune therapy with the aim of enhancing the response to immune therapy by the immunological mechanisms summarized in the term abscopal effect. This concept has also been investigated in less immunogenic tumors such as breast cancer. Initial data are promising but the hypothesis that the combination of checkpoint inhibitors and local radiotherapy could be an effective combination in breast cancer has to be proven by ongoing trials. Substitution of local radiotherapy by local hyperthermia could be an option in selected cases. Key Messages: Combination of checkpoint inhibitors with local radiation or hyperthermia in breast cancer is a promising approach and could enhance the response rates generated by immune therapy alone through the antitumor immune response initiated by the abscopal effect.

PurposeGiven the uncertainty surrounding the abscopal effect (AE), it is imperative to identify promising treatment targets. In this study, we aimed to explore the incidence of AE when administering radiotherapy to patients with oligoprogressive solid tumours while they are undergoing treatment with immune checkpoint inhibitors (ICIs).Materials and methodsIn this multicentre prospective observational study, oligoprogressive disease was defined as a < 20% increase in lesions compared to > 2 months before enrolment. We enrolled patients who requested radiotherapy during the ICI rest period between 2020 and 2023. AE was considered present if ≥ 1 non-irradiated lesion decreased by ≥ 30% before the next line of systemic therapy started.ResultsTwelve patients were included in this study; the common primary lesions were in the lungs (four patients) and kidneys (three patients). AEs were observed in six (50%) patients, with a median time to onset of 4 (range 2–9) months after radiotherapy. No significant predictors of AEs were identified. Patients in the AE group had a significantly better 1-year progression-free survival (PFS) rate than those in the non-AE group (p = 0.008). Two patients from the AE group were untreated and progression-free at the last follow-up. Four (33%) patients experienced grade 2 toxicity, with two cases attributed to radiotherapy and the other two to ICI treatment. No grade 3 or higher toxicities were observed in any category.ConclusionPatients with oligoprogressive disease may be promising targets with potential for AEs. AEs can lead to improved PFS and, in rare cases, to a certain progression-free period without treatment.Secondary Irradiating solid tumours in patients with oligoprogressive disease during immune checkpoint inhibitor therapy may be a promising target with the potential for abscopal effects (AEs). AEs can lead to improved progression-free survival and, in rare cases, to a certain progression-free period without treatment.

High Serum sPD-L1 Level Predicts Poor Outcome in Hepatocellular Carcinoma Patients Treated with Radiotherapy

Cancer immunotherapy exploits the immune system's ability to differentiate between tumor target cells and host cells. Except for limited success against a few tumor types, most immunotherapies have not achieved the desired clinical efficacy until recently. The field of cancer immunotherapy has flourished with a variety of new agents for clinical use, and remarkable progress has been made in the design of effective immunotherapeutic regimens. Furthermore, the therapeutic outcome of these novel agents is enhanced when combined with conventional cancer treatment modalities including radiotherapy (RT). An increasing number of studies have demonstrated the abscopal effect, an immunologic response occurring in cancer sites distant from irradiated areas. The present work reviews studies on the combination between RT and immunotherapy to induce synergistic and abscopal effects involved in cancer immunomodulation. Further insight into the complex interactions between the immune system and cancer cells in the tumor microenvironment, and their modulation by RT, may reveal the abscopal effect as a clinically relevant and reproducible event leading to improved cancer outcome.

Background: Malignant melanoma represents the deadliest form of skin cancer with a high tendency to metastasize during the early course of the disease. Radiation therapy has long played a key role in the management of both local and metastatic melanoma. Although local radiation therapy exerts antitumor effects by damaging the cellular DNA, it also induces an important out-of-field (distant) effect known as the “abscopal effect” in nonirradiated sites. Radiation therapy-induced abscopal effects are believed to be mediated by activation and stimulation of the immune system. Objective: To provide a detailed overview of the current state of knowledge and clinical experience of radiation therapy-induced abscopal effects in patients with malignant melanoma. Methods: Using electronic databases such as MEDLINE via PubMed and Google Scholar, a systematic literature review was performed to find published clinical evidence for radiation therapy-induced abscopal effects in patients with malignant melanoma. The clinical data on radiation therapy-induced abscopal effects were reviewed and the outcomes summarized. Results: Clinical evidence of patients with malignant melanoma was gathered using databases from MEDLINE and those findings were summarized. Although the precise mechanism of the abscopal effect of radiation therapy is still not completely understood, evidence suggests that tumor cell destruction by radiation releases tumor antigens that stimulate the immune system of the host to activate the body’s immune effector cells systemically and produce distant non-target antitumor effects. This forms a basis for using the radiation therapy with immunotherapy to augment the abscopal response rates. Conclusions: Current clinical evidence suggests that there is a large potential to enhance the abscopal effect when radiation therapy is combined with immunotherapeutic agents for the treatment of malignant melanoma. Ongoing and planned clinical trials may provide us with a more in-depth understanding of how this combination therapy can be optimally utilized clinically to achieve improved survival outcomes among patients with malignant melanoma.

Risk of Secondary Malignancies in Ovarian Cancer Survivors: 54,305 Patients Analyzed With 40 Years of Follow-up

Proposed approach for revealing unknown mediators of the abscopal effect

Contribution of the immune system to bystander and non-targeted effects of ionizing radiation

Abscopal Effect Following CT Guided Permanent Seed Brachytherapy for Metastatic Adenoid Cystic Carcinoma to Lung