Anti-Tumor Immunity and Preoperative Radiovaccination: Emerging New Concepts in the Treatment of Breast Cancer.

Neoadjuvant chemotherapy (NACT) for certain breast cancer (BC) subtypes confers significant tumor regression rates and a survival benefit for patients with a complete pathologic response. Clinical and preclinical studies have demonstrated that immune-related factors are responsible for better treatment outcomes, and thus, neoadjuvant immunotherapy (IO) has emerged as a means to further improve patient survival rates. Innate immunological "coldness", however, of specific BC subtypes, especially of the luminal ones, due to their immunosuppressive tumor microenvironment, hinders the efficacy of immune checkpoint inhibitors. Treatment policies aiming to reverse this immunological inertia are, therefore, needed. Moreover, radiotherapy (RT) has been proven to have a significant interplay with the immune system and promote anti-tumor immunity. This "radiovaccination" effect could be exploited in the neoadjuvant setting of BC and significantly enhance the effects of the already established clinical practice. Modern stereotactic irradiation techniques directed to the primary tumor and involved lymph nodes may prove important for the RT-NACT-IO combination. In this review, we provide an overview and critically discuss the biological rationale, clinical experience, and ongoing research underlying the interplay between neoadjuvant chemotherapy, anti-tumor immune response, and the emerging role of RT as a preoperative adjunct with immunological therapeutic implications in BC.

Radiovaccination Strategy for Cancer Treatment Integrating Photodynamic Therapy-Generated Vaccines with Radiotherapy.

Therapeutic cancer vaccines have become firmly established as a reliable and proficient form of tumor immunotherapy. They represent a promising approach for substantial advancements in the successful treatment of malignant diseases. One attractive vaccine strategy is using, as the vaccine material, the whole tumor cells treated ex vivo by rapid tumor ablation therapies that instigate stress signaling responses culminating in immunogenic cell death (ICD). One such treatment is photodynamic therapy (PDT). The underlying mechanisms and critical elements responsible for the potency of these vaccines are discussed in this review. Radiotherapy has emerged as a suitable component for the combined therapy protocols with the vaccines. Arguments and prospects for optimizing tumor control using a radiovaccination strategy involving X-ray irradiation plus PDT vaccines are presented, together with the findings supporting its validity.

The molecular basis of immuno-radiotherapy.

PURPOSE: Radiotherapy (RT) and immunotherapy are powerful anti-tumor treatment modalities. Experimental research has demonstrated an important interplay between the cytotoxic effects of RT and the immune system. This systematic review provides an overview of the basics of anti-tumor immunity and focuses on the mechanisms underlying the interplay between RT and immune anti-tumor response that set the molecular basis of immuno-RT. CONCLUSIONS: An 'immunity acquired equilibrium' mimicking tumor dormancy can be achieved post-irradiation treatment, with the balance shifted toward tumor eradication or regrowth when immune cells' cytotoxic effects or cancer proliferation rate prevail, respectively. RT has both immunosuppressive and immune-enhancing properties. The latter effect is also known as radio-vaccination. Its mechanisms involve up- or down-regulation of membrane molecules, such as PD-L1, HLA-class-I, CD80/86, CD47, and Fas/CD95, that play a vital role in immune checkpoint pathways and increased cytokine expression (e.g. INFα,ß,γ, IL1,2, and TNFα) by cancer or immune cells. Moreover, the interactions of radiation with the tumor microenvironment (fibroblasts, tumor-infiltrating lymphocytes, monocytes, and dendritic cells are also an important component of radio-vaccination. Thus, RT may have anti-tumor vaccine properties, whose sequels can be exploited by immunotherapy agents to treat different cancer subtypes effectively.

Radio-Immunotherapy: A Case Report of 'Abscopal Hyper-Progression'?

The radio-immunization effects of radiotherapy with abscopal tumor regressions have been documented in several experimental and clinical studies. Here, we present a patient with bladder cancer and relapsed metastatic disease to the left supraclavicular/axillary area and left lung. Concurrent weekly hypofractionated radiotherapy of both areas (8Gy/fraction/week, four fractions in total) and bi-weekly immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) monoclonal antibodies resulted in complete regression of the axillary metastatic masses and of the lung metastasis, three months after the onset of therapy. In CT scans, however, a sternum infiltrating mass growing proximal to the margins of the radiotherapy fields was strikingly evident, while multiple hepatic metastases also appeared. Lymphopenia during radio-immunotherapy was recorded. The current report does not confirm the abscopal effects of radio-immunotherapy and furthermore, suggests that progressive disease or even hyper-progression may occur in a subgroup of patients. Although radio-vaccination is a well-established phenomenon, it is evident that we still miss major aspects of host/tumor-immune interactions with radiation.

Radiovaccination Hypothesis.

The details of patients who have entered remission from metastatic melanoma following palliative radiotherapy are reported. We review the relevant immune physiology and radiotherapy particulars and propose the hypothesis that radiovaccination with high fractional dose to skin metastases can stimulate the development of a robust systemic anti-tumoral immune response capable of causing remission of metastatic disease.