Dataset Information

Immunologic Correlates of the Abscopal Effect in a SMARCB1/INI1-negative Poorly Differentiated Chordoma after EZH2 Inhibition and Radiotherapy.

ABSTRACT:

Purpose

We sought to determine the mechanism of an exceptional response in a patient diagnosed with a SMARCB1/INI1-negative chordoma treated with tazemetostat, an EZH2 inhibitor, and followed by radiotherapy.Patient and Methods: In an attempt to investigate the mechanism behind this apparent abscopal effect, we interrogated tumor tissues obtained over the clinical course. We utilized next-generation sequencing, standard IHC, and employed a novel methodology of multiplex immunofluorescence analysis.

Results

We report an exceptional and durable response (2+ years) in a patient with SMARCB1-deleted, metastatic, poorly differentiated chordoma, a lethal disease with an overall survival of 6 months. The patient was treated for 4 weeks with tazemetostat, an EZH2 inhibitor, in a phase II clinical trial. At the time of progression she underwent radiation to the primary site and unexpectedly had a complete response at distant metastatic sites. We evaluated baseline and on-treatment tumor biopsies and demonstrate that tazemetostat resulted in pharmacodynamic inhibition of EZH2 as seen by decrease in histone trimethylation at H3K27. Tazemetostat resulted in a significant increase in intratumoral and stromal infiltration by proliferative (high Ki-67), CD8⁺ T cells, FoxP3⁺ regulatory T cells, and immune cells expressing checkpoint regulators PD-1 and LAG-3. These changes were pronounced in the stroma.

Conclusions

These observations are the first demonstration in patient samples confirming that EZH2 inhibition can promote a sustained antitumor response that ultimately leads to T-cell exhaustion and checkpoint activation. This suggests that targeted alteration of the epigenetic landscape may sensitize some tumors to checkpoint inhibitors.

SUBMITTER: Gounder MM

PROVIDER: S-EPMC9165752 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Publications

Immunologic Correlates of the Abscopal Effect in a SMARCB1/INI1-negative Poorly Differentiated Chordoma after EZH2 Inhibition and Radiotherapy.

Gounder Mrinal M MM Zhu Guo G Roshal Lev L Lis Eric E Daigle Scott R SR Blakemore Steven J SJ Michaud Neil R NR Hameed Meera M Hollmann Travis J TJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20190114 7

<h4>Purpose</h4>We sought to determine the mechanism of an exceptional response in a patient diagnosed with a SMARCB1/INI1-negative chordoma treated with tazemetostat, an EZH2 inhibitor, and followed by radiotherapy.<b>Patient and Methods:</b> In an attempt to investigate the mechanism behind this apparent abscopal effect, we interrogated tumor tissues obtained over the clinical course. We utilized next-generation sequencing, standard IHC, and employed a novel methodology of multiplex immunofluo ...[more]

PMID: 30642912

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Project description:In the present study, a 36-year-old male presented with left scrotal enlargement without an obvious cause, accompanied by a feeling of heaviness. Imaging examinations revealed a left testicular malignancy, the patient underwent left testicular mass removal,and the postoperative pathology results revealed a highly malignant germ cell tumor, with a tendency toward poorly differentiated embryonal carcinoma or seminoma. After surgery, the condition of the patient deteriorated rapidly, and distant tumor metastasis occurred. Lymph node puncture pathology results revealed poorly differentiated carcinoma consistent with SMARCB1/INI-1 deletion. Despite the use of chemotherapy, radiotherapy, immunotherapy and targeted therapy, the patient died 11 months after surgery. To the best of our knowledge, this is the first case report of a SMARCB1/INI1-deficient Poorly differentiated testicular carcinoma, which is very similar to testicular spermatocytic carcinoma in clinical diagnosis and deserves differentiation for future clinical diagnoses.This report provides important insights into the diagnosis and treatment of SMARCB1/INI1-deficient testicular malignancy. SMARCB1 is a crucial tumor suppressor gene, and its deficiency is closely associated with the development of various malignant tumors. The identification of this case suggests that future research should further explore the molecular mechanisms of SMARCB1-deficient tumors, particularly their role in testicular malignancies. Additionally, the diagnostic process of this case highlights that SMARCB1/INI1-deficient tumors can be clinically very similar to spermatocytic carcinoma of the testis, which can easily lead to misdiagnosis. Therefore, future clinical practice should emphasize the detection of SMARCB1/INI1 expression status, especially in the context of highly aggressive and rapidly progressing testicular malignancies, where immunohistochemical testing for SMARCB1/INI1 should be considered to confirm the diagnosis. In terms of treatment, this case demonstrates the highly aggressive nature and resistance to conventional therapies of SMARCB1/INI1-deficient tumors. Despite the patient receiving multiple treatments, disease progression could not be halted. This underscores the need for the development of novel therapeutic strategies targeting SMARCB1/INI1-deficient tumors, such as combinations of immune checkpoint inhibitors and targeted therapies, or other emerging immunotherapeutic approaches. Moreover, the treatment course of this patient also reflects the importance of individualized treatment plans. Future research should further explore precision medicine strategies based on tumor genetic profiles to improve patient survival rates and quality of life.

Dataset Information

Immunologic Correlates of the Abscopal Effect in a SMARCB1/INI1-negative Poorly Differentiated Chordoma after EZH2 Inhibition and Radiotherapy.

Purpose

Results

Conclusions

Publications

Immunologic Correlates of the Abscopal Effect in a SMARCB1/INI1-negative Poorly Differentiated Chordoma after EZH2 Inhibition and Radiotherapy.

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