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Radiation therapy (RT) is a pillar of cancer therapy used by more than half of all cancer patients. Clinically, RT is mostly delivered as external beam radiation therapy (EBRT). However, the scope of EBRT is limited in the metastatic setting, where all sites of disease need to be irradiated. Such a limitation is attributed to radiation-induced toxicities, for example on bone marrow and hematologic toxicities, resulting from a large EBRT field. Radiopharmaceutical therapy (RPT) has emerged as an alternative to EBRT for the irradiation of all sites of metastatic disease. While RPT can reduce tumor burden, it can also impact the immune system and anti-tumor immunity. Understanding these effects is crucial for predicting and managing treatment-related hematological toxicities and optimizing their integration with other therapeutic modalities, such as immunotherapies. Here, we review the immunomodulatory effects of α- and β-particle emitter-based RPT on various immune cell lines, such as CD8+and CD4+ T cells, natural killer (NK) cells, and regulatory T (Treg) cells. We briefly discuss Auger electron-emitter (AEE)-based RPT, and finally, we highlight the combination of RPT with immune checkpoint inhibitors, which may offer potential therapeutic synergies for patients with metastatic cancers. [ABSTRACT FROM AUTHOR]

The degree to which disability benefit programs provide an adequate standard of living to those with work-limiting disabilities has long been overlooked in social policy research. This paper presents a framework for assessing disability-related decommodification and then applies that framework to an analysis of the Social Security Disability (SSD) programs in the United States. The paper draws on survey data from the Health and Retirement Study linked to administrative records from the Social Security Administration, and further compares the U.S. estimates to those from 27 other countries. The results indicate that more than 50 percent of older adults of working-age with work-disabilities in the U.S. do not receive SSD benefits, though rates of benefit receipt are higher than the average across other high-income countries. Those that receive SSD benefits, moreover, experience greater difficulty achieving an adequate standard of living, as measured by an index of financial security, than those with similar characteristics in the U.S. who do not receive disability benefits. The paper thus provides a framework for future policy research on benefit adequacy, while evaluating the availability and generosity of disability benefits in the U.S. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT) activates multiple immunologic effects in the tumor microenvironment (TME), with diverse dose-response relationships observed. We hypothesized that, in contrast with homogeneous RT, a heterogeneous RT dose would simultaneously optimize activation of multiple immunogenic effects in a single TME, resulting in a more effective antitumor immune response. Using high-dose-rate brachytherapy, we treated mice bearing syngeneic tumors with a single fraction of heterogeneous RT at a dose ranging from 2 to 30 gray. When combined with dual immune checkpoint inhibition in murine models, heterogeneous RT generated more potent antitumor responses in distant, nonirradiated tumors compared with any homogeneous dose. The antitumor effect after heterogeneous RT required CD4 and CD8 T cells and low-dose RT to a portion of the tumor. At the 3-day post-RT time point, dose heterogeneity imprinted the targeted TME with spatial differences in immune-related gene expression, antigen presentation, and susceptibility of tumor cells to immune-mediated destruction. At a later 10-day post-RT time point, high-, moderate-, or low-RT-dose regions demonstrated distinct infiltrating immune cell populations. This was associated with an increase in the expression of effector-associated cytokines in circulating CD8 T cells. Consistent with enhanced adaptive immune priming, heterogeneous RT promoted clonal expansion of effector CD8 T cells. These findings illuminate the breadth of dose-dependent effects of RT on the TME and the capacity of heterogeneous RT to promote antitumor immunity when combined with immune checkpoint inhibitors. Editor's summary: Radiation therapy (RT) is usually administered as a single dose across a tumor. However, not all radiation doses are created equal. High radiation doses promote immunogenic cell death, medium radiation doses promote type I interferon responses, and low radiation doses promote inflammatory cytokine production and immune cell trafficking. To reap the benefits of all three doses, Jagodinsky et al. treated murine tumors with heterogeneous RT, where different regions of the tumor were treated with different RT doses. The authors found that this heterogeneous approach outperformed homogeneous dose RT in a T cell–dependent manner and could be combined with immune checkpoint inhibition. These data support further clinical development of heterogeneous RT. —Courtney Malo [ABSTRACT FROM AUTHOR]

Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen. Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti-CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects. Results: Tumors with volumes of 2,000 mm³ or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory. Conclusions: These findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors. [ABSTRACT FROM AUTHOR]

Radiotherapy elicits dose- and lineage-dependent effects on immune cell survival, migration, activation, and proliferation in targeted tumor microenvironments. Radiation also stimulates phenotypic changes that modulate the immune susceptibility of tumor cells. This has raised interest in using radiotherapy to promote greater response to immunotherapies. To clarify the potential of such combinations, it is critical to understand how best to administer radiation therapy to achieve activation of desired immunologic mechanisms. In considering the multifaceted process of priming and propagating anti-tumor immune response, radiation dose heterogeneity emerges as a potential means for simultaneously engaging diverse dose-dependent effects in a single tumor environment. Recent work in spatially fractionated external beam radiation therapy demonstrates the expansive immune responses achievable when a range of high to low dose radiation is delivered in a tumor. Brachytherapy and radiopharmaceutical therapies deliver inherently heterogeneous distributions of radiation that may contribute to immunogenicity. This review evaluates the interplay of radiation dose and anti-tumor immune response and explores emerging methodological approaches for investigating the effects of heterogeneous dose distribution on immune responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Low-dose radiation delivered by radionuclides stimulates an immune response against cancer. We hypothesize that this type of low-dose radiation can potentiate chimeric antigen receptor (CAR) T cell therapy against solid tumors. Before evaluating the combination of these therapies in vivo, we aim to determine the impacts of this type of low-dose radiation on CAR T cell viability and functions to guide the selection of the type of radionuclide (actinium-225 or lutetium-177), the dose of radiation (1, 2 or 6 Gy) and how to best sequence their administration. It follows that increasing the radiation dose results in lower CAR T cell viability while enhancing their killing potential to the same extent. At a similar dose, radiation delivered by actinium-225 is more toxic to CAR T cells than lutetium-177. This suggests that 1 or 2 Gy delivered by lutetium-177 may be optimal for in vivo combination studies with CAR T cells. Background and purpose. Chimeric antigen receptor (CAR) T cells have been relatively ineffective against solid tumors. Low-dose radiation which can be delivered to multiple sites of metastases by targeted radionuclide therapy (TRT) can elicit immunostimulatory effects. However, TRT has never been combined with CAR T cells against solid tumors in a clinical setting. This study investigated the effects of radiation delivered by Lutetium-177 (177Lu) and Actinium-225 (225Ac) on the viability and effector function of CAR T cells in vitro to evaluate the feasibility of such therapeutic combinations. After the irradiation of anti-GD2 CAR T cells with various doses of radiation delivered by 177Lu or 225Ac, their viability and cytotoxic activity against GD2-expressing human CHLA-20 neuroblastoma and melanoma M21 cells were determined by flow cytometry. The expression of the exhaustion marker PD-1, activation marker CD69 and the activating receptor NKG2D was measured on the irradiated anti-GD2 CAR T cells. Both 177Lu and 225Ac displayed a dose-dependent toxicity on anti-GD2 CAR T cells. However, radiation enhanced the cytotoxic activity of these CAR T cells against CHLA-20 and M21 irrespective of the dose tested and the type of radionuclide. No significant changes in the expression of PD-1, CD69 and NKG2D was noted on the CAR T cells following irradiation. Given a lower CAR T cell viability at equal doses and an enhancement of cytotoxic activity irrespective of the radionuclide type, 177Lu-based TRT may be preferred over 225Ac-based TRT when evaluating a potential synergism between these therapies in vivo against solid tumors. [ABSTRACT FROM AUTHOR]

Therapies against cell-surface targets (CSTs) represent an emerging treatment class in solid malignancies. However, high-throughput investigations of CST expression across cancer types have been reliant on data sets of mostly primary tumors, despite therapeutic use most commonly in metastatic disease. We identified a total of 818 clinical trials of CST therapies with 78 CSTs. We assembled a data set spanning RNA-seq and microarrays in 7,927 benign samples, 16,866 primary tumor samples, and 6,124 metastatic tumor samples. We also utilized single-cell RNA-seq data from 36 benign tissues and 558 primary and metastatic tumor samples, and matched RNA versus protein expression in 29 benign tissue samples, 1,075 tumor samples, and 942 cell lines. High RNA expression accurately predicted high protein expression across CST therapies in benign tissues, tumor samples, and cell lines. We compared metastatic versus primary tumor expression, identified potential opportunities for repositioning, and matched cell lines to tumor types based on CST and global RNA expression. We evaluated single-cell heterogeneity across tumors, and identified rare normal cell subpopulations that may contribute to toxicity. Finally, we identified combinations of CST therapies for which bispecific approaches could improve tumor specificity. This study helps better define the landscape of CST expression in metastatic and primary cancers.

Population-scale databases have expanded to millions of protein-coding variants, yet insight into their mechanistic consequences has lagged. Here we present PROD-ATAC, a high-throughput method for discovering the effects of protein-coding variants on chromatin regulation. A pooled variant library is expressed in a disease-agnostic cell line, and single-cell assay for transposase-accessible chromatin resolves each variant's effect on the chromatin landscape. Using PROD-ATAC, we characterized the effects of more than 100 oncofusions (cancer-causing chimeric proteins) and controls and revealed that chromatin remodeling is common to fusions spanning an enormous range of fusion frequencies. Furthermore, fusion-induced dysregulation can be context agnostic, as observed mechanisms often overlapped with cancer and cell-type-specific prior knowledge. We also showed that gain-of-function activity is common among oncofusions. This work begins to outline a global map of fusion-induced chromatin alterations. We suggest that there might be convergent mechanisms among disparate oncofusions and shared modes of dysregulation among fusions present in tumors at different frequencies. PROD-ATAC is generalizable to any set of protein-coding variants., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Radiopharmaceutical therapies (RPT) activate a type I interferon (IFN1) response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by 90 Y, 177 Lu, and 225 Ac in vitro as unbound radionuclides and in vivo when chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by qPCR and flow cytometry. Therapeutic response to 225 Ac-NM600+anti-CTLA4+anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of interferon genes knockout (STING KO) B78. The timing and magnitude of IFN1 response correlated with radionuclide half-life and linear energy transfer. CD8 + /Treg ratios increased in tumors 7 days after 90 Y- and 177 Lu-NM600 and day 21 after 225 Ac-NM600. 225 Ac-NM600+ICI improved survival in mice with WT but not with STING KO tumors, relative to monotherapies. Immunomodulatory effects of RPT vary with radioisotope and promote STING-dependent enhanced response to ICIs in murine models., Teaser: This study describes the time course and nature of tumor immunomodulation by radiopharmaceuticals with differing physical properties.

Rationale: Androgen deprivation therapy (ADT) is pivotal in treating recurrent prostate cancer and is often combined with external beam radiation therapy (EBRT) for localized disease. However, for metastatic castration-resistant prostate cancer, EBRT is typically only used in the palliative setting, because of the inability to radiate all sites of disease. Systemic radiation treatments that preferentially irradiate cancer cells, known as radiopharmaceutical therapy or targeted radionuclide therapy (TRT), have demonstrable benefits for treating metastatic prostate cancer. Here, we explored the use of a novel TRT, 90 Y-NM600, specifically in combination with ADT, in murine prostate tumor models., Methods: 6-week-old male FVB mice were implanted subcutaneously with Myc-CaP tumor cells and given a single intravenous injection of 90 Y-NM600, in combination with ADT (degarelix). The combination and sequence of administration were evaluated for effect on tumor growth and infiltrating immune populations were analyzed by flow cytometry. Sera were assessed to determine treatment effects on cytokine profiles., Results: ADT delivered prior to TRT (ADT→TRT) resulted in significantly greater antitumor response and overall survival than if delivered after TRT (TRT→ADT). Studies conducted in immunodeficient NRG mice failed to show a difference in treatment sequence, suggesting an immunological mechanism. Myeloid-derived suppressor cells (MDSCs) significantly accumulated in tumors following TRT→ADT treatment and retained immune suppressive function. However, CD4+ and CD8+ T cells with an activated and memory phenotype were more prevalent in the ADT→TRT group. Depletion of Gr1+MDSCs led to greater antitumor response following either treatment sequence. Chemotaxis assays suggested that tumor cells secreted chemokines that recruited MDSCs, notably CXCL1 and CXCL2. The use of a selective CXCR2 antagonist, reparixin, further improved antitumor responses and overall survival when used in tumor-bearing mice treated with TRT→ADT., Conclusion: The combination of ADT and TRT improved antitumor responses in murine models of prostate cancer, however, this was dependent on the order of administration. This was found to be associated with one treatment sequence leading to an increase in infiltrating MDSCs. Combining treatment with a CXCR2 antagonist improved the antitumor effect of this combination, suggesting a possible approach for treating advanced human prostate cancer., Competing Interests: Competing interests: JPW is a co-founder and Senior Science Advisor for Archeus Technologies, which holds the license rights to NM600-related technologies. ZSM and RH have financial interest in Archeus Technologies. HCR has served as a consultant for Archeus Technologies. ZSM is a member of the Scientific Advisory Boards for Archeus Technologies, Seneca Therapeutics, and NorthStar Medical Isotopes. ZSM is an inventor on patents or filed patents managed by the Wisconsin Alumni Research Foundation relating to immunotherapies and the interaction of targeted radionuclide therapies and immunotherapies. The other authors have no relevant potential conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)