Evaluation of radio-immunotherapy sequence on immunological responses and clinical outcomes in patients with melanoma brain metastases (ELEKTRA)

Hassel, Jessica C.; Schank, Timo E; Smetak, Heiko; Mühlbauer, Jasmin; Salzmann, Martin; Machiraju, Devayani; Menzer, Christian; Lang, Kristin; König, Laila; Haefner, Matthias F.; Hülsmeyer, Ingrid; Köhler, Christian; Spang, Rainer; Enk, Alexander H.; Debus, Jürgen; Beckhove, Philipp

doi:10.1080/2162402x.2022.2066609

Cited by 15 publications

(13 citation statements)

References 48 publications

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“…The CD45RA is expressed on naive T cells, which respond poorly to recall antigens, and when activated by a foreign or tumor antigen, they lose expression of the CD45RA (25). Increased frequencies of CD45RA-memory T cells were previously shown to be associated with better responses to ICIs in melanoma patients (16). Therefore, the lower frequencies of these T cells in the blood may suggest the absence of tumor-specific T cell memory in younger patients required for a successful ICI treatment.…”

Section: Discussionmentioning

confidence: 99%

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Rapid disease progression on immune checkpoint inhibitors in young patients with stage IV melanoma

et al. 2023

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BackgroundImmune checkpoint inhibitors (ICIs) are the standard of care for metastatic cutaneous melanoma (mCM) patients, but their efficacy in young adults aged less than 40 years remains unclear.Materials and methodsWe retrospectively analyzed 303 stage IV melanoma patients of different ages treated with nivolumab, pembrolizumab, or ipilimumab plus nivolumab combination therapy. Clinical data and blood values such as LDH, CRP, and absolute immune cell counts were retrieved from the medical records. Pre-treatment serum concentrations of soluble immune checkpoint proteins were measured using ELISA. In addition, information on frequencies of various T cell subsets in the peripheral blood was collected from a previously reported study (ELEKTRA). Patient characteristics and clinical information was correlated with PFS and OS using univariate and multivariate cox regression analysis.ResultsOf 303 patients, 33 (11%) were ≤ 40 years old. The older patients had a median age of 64 (95% CI: 61–66). Concerning prognostic parameters, there was no difference between the age groups, e.g., in gender, LDH, or the existence of brain or liver metastases. Patients aged ≤ 40 years [p = 0.014; HR: 1.6 (95% CI: 1.1–2.4)], presence of liver metastases [p = 0.016; HR: 1.4 (95% CI: 1.0–1.9)], line of ICI treatment [p = 0.009; HR: 1.4 (1.0–1.9)], elevated LDH [p = 0.076; HR: 1.3 (95% CI: 0.97–1.8)], and brain metastasis [p = 0.080; HR: 1.3 (95% CI: 0.97–1.7)], were associated with shorter PFS in univariate analysis. Multivariate analysis revealed that the patient’s age (≤ 40 years) remains a high-risk factor upon adjusting for all potential confounders [p = 0.067; HR: 1.5 (95% CI: 0.97–2.3)]. Blood parameters revealed that patients ≤ 40 years have relatively higher frequencies of activated CD4 T cells (CD4 + Ki67 + CD4 + ICOS +) in the blood, and significantly lower number of basophils and CD45RA- memory T cells, compared to patients above 40 years (p < 0.05). In addition, patients ≤ 40 years experiencing disease progression within 6 months of ICI treatment had increased concentrations of sPDL1 (p = 0.05) and sTIM3 (p = 0.054) at baseline.ConclusionYoung patients with stage IV melanoma may experience shorter progression-free survival upon ICI treatment compared to patients above 40 years and are characterized by fewer basophils and memory T cells in the blood.

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Section: Discussionmentioning

confidence: 99%

“…Flow cytometric data of peripheral T-cell frequencies were collected from a previously reported study (ELEKTRA) ( 16 ). The information on frequencies of peripheral T cell subsets in patients with stage IV skin cancer at baseline is available from 71 patients from the ELEKTRA study.…”

Section: Methodsmentioning

confidence: 99%

Rapid disease progression on immune checkpoint inhibitors in young patients with stage IV melanoma

et al. 2023

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“…Identification of the optimal sequencing strategy has been performed retrospectively and comprehensive meta-analysis of the accumulated clinical evidence suggested superiority of concurrent over sequential ICI and RT treatment (121). In contrast to the retrospective observations, the prospective single institution ELEKTRA trial demonstrated superiority of RT given prior to ICI treatment, which was reflected by more pronounced increases in circulating CD4 and CD8 cell populations (122). These discrepancies may be related with confounding factors, affecting conclusions of the retrospective trials (122).…”

Section: Clinical Usage Of Radio-and Immunotherapiesmentioning

confidence: 90%

“…In contrast to the retrospective observations, the prospective single institution ELEKTRA trial demonstrated superiority of RT given prior to ICI treatment, which was reflected by more pronounced increases in circulating CD4 and CD8 cell populations (122). These discrepancies may be related with confounding factors, affecting conclusions of the retrospective trials (122).…”

Section: Clinical Usage Of Radio-and Immunotherapiesmentioning

confidence: 90%

Combination of immune checkpoint inhibitors with radiation therapy in cancer: A hammer breaking the wall of resistance

Voronova¹,

Vislobokova²,

Mutig³

et al. 2022

Front. Oncol.

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Immuno-oncology is an emerging field in the treatment of oncological diseases, that is based on recruitment of the host immune system to attack the tumor. Radiation exposure may help to unlock the potential of the immune activating agents by enhancing the antigen release and presentation, attraction of immunocompetent cells to the inflammation site, and eliminating the tumor cells by phagocytosis, thereby leading to an overall enhancement of the immune response. Numerous preclinical studies in mouse models of glioma, murine melanoma, extracranial cancer, or colorectal cancer have contributed to determination of the optimal radiotherapy fractionation, as well as the radio- and immunotherapy sequencing strategies for maximizing the antitumor activity of the treatment regimen. At the same time, efficacy of combined radio- and immunotherapy has been actively investigated in clinical trials of metastatic melanoma, non-small-cell lung cancer and renal cell carcinoma. The present review summarizes the current advancements and challenges related to the aforementioned treatment approach.

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“…The authors also noted that anti-PD-1 agents resulted in a greater median volume reduction than their anti-CTLA-4 counterparts. The prospective non-randomized phase 2 study, ELEKTRA, is a considerable investigation into the effects of combination therapies such as pre-ICIs-RT or pre-RT-ICIs on antitumor and peripheral T cell responses in MM patients with brain metastasis(46). Patients with brain metastasis received RT (WBRT or SRS depending on the number of brain metastasis ) in two different sequences in combination with NIVOIPI (RT before or after ICIs).…”

mentioning

confidence: 99%

Combined Stereotactic Radiosurgery and Immune Checkpoint Inhibitors for the Treatment of Brain Metastasis

Küçük

Topkan

Durankus

et al. 2023

Advancements in Cancer Research

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Metastasis of solid tumors to the brain occurs in about 30% of cases. Surgery and whole-brain radiotherapy have been the standard treatments with very limited success rates. As a result of the unsatisfactory local control and longterm survival outcomes, stereotactic radiosurgery has been used as an alternative to surgery and whole-brain radiotherapy, or to improve the outcomes in conjunction with other treatments. However, stereotactic radiosurgery does not produce the desired survival results despite the striking increases in local control rates, primarily because of deaths attributed to extracranial systemic disease progression or unavoidably fatal distant brain recurrences. Lately, immunotherapy has become Kucuk A et al. 58a part, or mainstay, of treatment algorithms for many cancer types. Several authors have proposed the integration of stereotactic radiosurgery and immunotherapy for the treatment of brain metastasis. This chapter evaluates the efficacy and safety of combining novel immunotherapeutics with traditional stereotactic radiosurgery for the treatment of brain metastasis.

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Evaluation of radio-immunotherapy sequence on immunological responses and clinical outcomes in patients with melanoma brain metastases (ELEKTRA)

Cited by 15 publications

References 48 publications

Rapid disease progression on immune checkpoint inhibitors in young patients with stage IV melanoma

Rapid disease progression on immune checkpoint inhibitors in young patients with stage IV melanoma

Combination of immune checkpoint inhibitors with radiation therapy in cancer: A hammer breaking the wall of resistance

Combined Stereotactic Radiosurgery and Immune Checkpoint Inhibitors for the Treatment of Brain Metastasis

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