Can Radiotherapy Empower the Host Immune System to Counterattack Neoplastic Cells? A Systematic Review on Tumor Microenvironment Radiomodulation

Iori, Federico; Bruni, Alessio; Cozzi, Salvatore; Ciammella, Patrizia; Pressa, Francesca Di; Boldrini, Luca; Greco, Carlo; Nardone, Valerio; Salvestrini, Viola; Desideri, Isacco; Felice, Francesca De; Iotti, C.

doi:10.3390/curroncol29070366

Cited by 7 publications

(6 citation statements)

References 35 publications

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“…Emerging data have established RT as a useful therapeutic option also for oligometastatic and oligorecurrent/oligoprogressive disease [16], rare histologies [17,18], or in combination with new drugs available for hormone-sensitive and castration-resistant PC. In recent years, advances in radiation planning and delivery techniques, in particular the advent of new-generation linac with the FFF mode, have improved treatment accuracy and given rise to the adoption of ultrahypofractionated radiation schedules in the form of SBRT [19] in different oncological settings, with acceptable toxicity [20][21][22][23][24][25]. Despite this, local failure after RT still remains a critical issue.…”

Section: Discussionmentioning

confidence: 99%

Linac-based stereotactic salvage reirradiation for intraprostatic prostate cancer recurrence: toxicity and outcomes

Cozzi

Ghersi

Bardoscia³

et al. 2023

Strahlenther Onkol

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Background The rates of local failure after curative radiotherapy for prostate cancer (PC) remain high despite more accurate locoregional treatments available, with one third of patients experiencing biochemical failure and clinical relapse occurring in 30–47% of cases. Today, androgen deprivation therapy (ADT) is the treatment of choice in this setting, but with not negligible toxicity and low effects on local disease. Therefore, the treatment of intraprostatic PC recurrence represents a challenge for radiation oncologists. Prostate reirradiation (Re-I) might be a therapeutic possibility. We present our series of patients treated with salvage stereotactic Re‑I for intraprostatic recurrence of PC after radical radiotherapy, with the aim of evaluating feasibility and safety of linac-based prostate Re‑I. Materials and methods We retrospectively evaluated toxicities and outcomes of patients who underwent salvage reirradiation using volumetric modulated arc therapy (VMAT) for intraprostatic PC recurrence. Inclusion criteria were age ≥ 18 years, histologically proven diagnosis of PC, salvage Re‑I for intraprostatic recurrence after primary radiotherapy for PC with curative intent, concurrent/adjuvant ADT with stereotactic body radiation therapy (SBRT) allowed, performance status ECOG 0–2, restaging choline/PSMA-PET/TC and prostate MRI after biochemical recurrence, and signed informed consent. Results From January 2019 to April 2022, 20 patients were recruited. Median follow-up was 26.7 months (range 7–50). After SBRT, no patients were lost at follow-up and all are still alive. One- and 2‑year progression free survival (PFS) was 100% and 81.5%, respectively, while 2‑year biochemical progression-free survival (bFFS) was 88.9%. Four patients (20%) experienced locoregional lymph node progression and were treated with a further course of SBRT. Prostate reirradiation allowed the ADT start to be postponed for 12–39 months. Re‑I was well tolerated by all patients and none discontinued the treatment. No cases of ≥ G3 genitourinary (GU) or gastrointestinal (GI) toxicity were reported. Seven (35%) and 2 (10%) patients experienced acute G1 and G2 GU toxicity, respectively. Late GU toxicity was recorded in 10 (50%) patients, including 8 (40%) G1 and 2 (10%) G2. ADT-related side effects were found in 7 patients (hot flashes and asthenia). Conclusion Linac-based SBRT is a safe technique for performing Re‑I for intraprostatic recurrence after primary curative radiotherapy for PC. Future prospective, randomized studies are desirable to better understand the effectiveness of reirradiation and the still open questions in this field.

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Section: Discussionmentioning

confidence: 99%

Linac-based stereotactic salvage reirradiation for intraprostatic prostate cancer recurrence: toxicity and outcomes

Cozzi

Ghersi

Bardoscia³

et al. 2023

Strahlenther Onkol

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“…However, this inflammatory response induced by SBRT may not be durable since an immunosuppressive cascade can also be triggered by SBRT. 30 31 One such mechanism is generating immunosuppressive adenosine from extracellular ATP released from irradiated tumor cells. We demonstrated that systemic administration of anti-CD73 and anti-PD-L1 greatly augmented local SBRT-induced antitumor efficacy in both mouse orthotopic and metastatic models.…”

Section: Discussionmentioning

confidence: 99%

CD73 and PD-L1 dual blockade amplifies antitumor efficacy of SBRT in murine PDAC models

Gavras

Keeley

et al. 2023

J Immunother Cancer

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BackgroundStereotactic body radiotherapy (SBRT) induces immunogenic cell death, leading to subsequent antitumor immune response that is in part counterbalanced by activation of immune evasive processes, for example, upregulation of programmed cell death-ligand 1 (PD-L1) and adenosine generating enzyme, CD73. CD73 is upregulated in pancreatic ductal adenocarcinoma (PDAC) compared with normal pancreatic tissue and high expression of CD73 in PDACs is associated with increased tumor size, advanced stage, lymph node involvement, metastasis, PD-L1 expression and poor prognosis. Therefore, we hypothesized that blockade of both CD73 and PD-L1 in combination with SBRT might improve antitumor efficacy in an orthotopic murine PDAC model.MethodsWe assessed the combination of systemic blockade of CD73/PD-L1 and local SBRT on tumor growth in primary pancreatic tumors, and investigated systemic antitumor immunity using a metastatic murine model bearing both orthotopic primary pancreatic tumor and distal hepatic metastases. Immune response was quantified by flow cytometric and Luminex analyses.ResultsWe demonstrated that blockade of both CD73 and PD-L1 significantly amplified the antitumor effect of SBRT, leading to superior survival. The triple therapy (SBRT+anti-CD73+anti-PD-L1) modulated tumor-infiltrating immune cells with increases of interferon-γ+CD8+T cells. Additionally, triple therapy reprogramed the profile of cytokines/chemokines in the tumor microenvironment toward a more immunostimulatory phenotype. The beneficial effects of triple therapy are completely abrogated by depletion of CD8+T cells, and partially reversed by depletion of CD4+T cells. Triple therapy promoted systemic antitumor responses illustrated by: (1) potent long-term antitumor memory and (2) enhanced both primaryandliver metastases control along with prolonged survival.

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“…This may happen because tumor-antigen release induced by radiations can activate an immune response directed against the antigen itself [ 53 , 54 ]. The addition of radiotherapy to immunotherapy allows for the boosting of the immune system, stimulating the release of immunogenic tumor-specific antigens and depleting intratumoral T regs , thus encouraging the idea that the combination of radiotherapy with immunotherapy may strengthen the anti-tumor immune response both locally and systemically (the so-called abscopal effect) [ 55 , 56 ].…”

Section: Combining Immunotherapy and Ionizing Radiation For Sclcmentioning

confidence: 99%

Dissecting Immunotherapy Strategies for Small Cell Lung Cancer: Antibodies, Ionizing Radiation and CAR-T

Guaitoli

Neri

Cabitza

et al. 2022

IJMS

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Small cell lung cancer (SCLC) is a highly aggressive malignancy that accounts for about 14% of all lung cancers. Platinum-based chemotherapy has been the only available treatment for a long time, until the introduction of immune checkpoint inhibitors (ICIs) recently changed first-line standard of care and shed light on the pivotal role of the immune system. Despite improved survival in a subset of patients, a lot of them still do not benefit from first-line chemo-immunotherapy, and several studies are investigating whether different combination strategies (with both systemic and local treatments, such as radiotherapy) may improve patient outcomes. Moreover, research of biomarkers that may be used to predict patients’ outcomes is ongoing. In addition to ICIs, immunotherapy offers other different strategies, including naked monoclonal antibodies targeting tumor associated antigens, conjugated antibody, bispecific antibodies and cellular therapies. In this review, we summarize the main evidence available about the use of immunotherapy in SCLC, the rationale behind combination strategies and the studies that are currently ongoing in this setting, in order to give the reader a clear and complete view of this rapidly expanding topic.

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Can Radiotherapy Empower the Host Immune System to Counterattack Neoplastic Cells? A Systematic Review on Tumor Microenvironment Radiomodulation

Cited by 7 publications

References 35 publications

Linac-based stereotactic salvage reirradiation for intraprostatic prostate cancer recurrence: toxicity and outcomes

Linac-based stereotactic salvage reirradiation for intraprostatic prostate cancer recurrence: toxicity and outcomes

CD73 and PD-L1 dual blockade amplifies antitumor efficacy of SBRT in murine PDAC models

Dissecting Immunotherapy Strategies for Small Cell Lung Cancer: Antibodies, Ionizing Radiation and CAR-T

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