Pathologic and Immunologic Response After Ablative Radiation in Lung Cancer

Non-small Cell Lung Cancer Stage I Clinical Trial

Official title:

Studying the Pathologic and Immunologic Response After Ablative Radiation in Stage I Non-Small Cell Lung Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03603002
• Other study ID #: J1826
• Secondary ID: IRB00163415
• Status: Active, not recruiting
• Phase: N/A
• Start date: October 16, 2018
• Est. completion date: December 2024

Study information

• Verified date: April 2024
• Source: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a pilot study to compare pre- and post-SABR core biopsies of stage I NSCLC tumors to identify SABR-induced immune-mediated tumor recognition based on a significant and specific expansion of T-cell clones using a novel T-cell receptor (TCR) sequencing assay. This will be coupled with (1) novel genomic analysis of candidate tumor antigens that may be released from the pre-SABR tumor and (2) functional validation assays to screen post-treatment peripheral blood T-cells for reactivity to these released candidate tumor antigens. In addition, cell-based analysis will be used to identify changes in key T-cell infiltrates into the post-SABR tumor.

Description:

Lung cancer is the leading cause of cancer death in the United States. While stereotactic ablative radiotherapy (SABR) is delivered as standard treatment in patients with medically inoperable stage I non-small cell lung cancer (NSCLC), an alarming 30-40% of these patients still develop disease recurrence just outside of the radiation field and deadly distant metastases in their lifetime. Furthermore, since the abscopal response was reported in advanced NSCLC where a systemic cancer response was induced in areas away from the irradiated site when radiation was combined with immunotherapy, multiple clinical trials are currently investigating the role of combining these two modalities. Significantly, how SABR alone increases immunogenicity of a tumor is unknown. There is a critical need to elucidate the mechanism by which SABR alone incites the immune system to better develop future rational combinations of immunotherapy with SABR.

SABR induced cell death will ultimately activate downstream cytotoxic T-cells and cause T-cell influx into the tumor to enhance immunogenic tumor cell kill. This is accomplished with SABR-induced tumor antigen-both mutation-associated neoantigen and tumor-associated antigen- release, priming of downstream cytotoxic T-cells, leading to specific T-cell clonal expansion, and resultant influx of these activated cytotoxic T-cells into the tumor and blood to enhance immune-mediated tumor cell kill.

Herein the investigator proposes a pilot study to compare pre- and post-SABR core biopsies of stage I NSCLC tumors to identify SABR-induced immune-mediated tumor recognition based on a significant and specific expansion of T-cell clones using a novel T-cell receptor (TCR) sequencing assay. This will be coupled with (1) novel genomic analysis of candidate tumor antigens that may be released from the pre-SABR tumor and (2) functional validation assays to screen post-treatment peripheral blood T-cells for reactivity to these released candidate tumor antigens. In addition, cell-based analysis will be used to identify changes in key T-cell infiltrates into the post-SABR tumor.

The results of this pilot study may have the potential to translate into improved systemic outcomes for patients with NSCLC through future integrated trials of immune checkpoint blockade antibodies that specifically relieve the immunosuppression on the T-cell population found to be activated by SABR. Clarifying SABR-induced immune changes in the tumor and blood will identify pathways that may be exploited to enhance systemic immunity to kill micro-metastatic disease and mitigate relapse in the next generation of clinical trials.

Additional corollary imaging studies using dual-energy (DE) computed tomography (CT), a novel imaging modality that improves the material decomposition ability of CTs, may identify new imaging markers for post-SABR treatment response by comparing DE-CT imaging characteristics with SABR fields and pathologic response.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 6
• Est. completion date: December 2024
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

Inclusion Criteria:

• Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations

• Age > 18 year

• Confirmed non-small cell lung cancer after initial biopsies

• Patient with accessible tumor for biopsy

• Patient is to have sufficient initial core biopsy samples for tissue analyses

• Stage I lung cancer

• Adequate normal organ and marrow function

• Patient with tumor amenable to SABR treatment as determined by a radiation oncologist

• Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

• Post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal subjects. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.

Exclusion Criteria:

• Primary tumors not amenable to serial core biopsies.

• Prior thoracic radiation in the region that will be treated by SABR.

• Patient may not be receiving any other concurrent investigational agents or chemotherapy.

• Patient may not be receiving or received immunotherapy.

• Patients may not be on or use steroids within 14 days before radiation, and from the duration of radiation to the time of the post-SABR biopsies and blood samples.

• Female patients who are pregnant from screening to completion of SABR

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer Stage I

Intervention

Diagnostic Test:
• Post-SABR Biopsy
Post-SABR Biopsy

Locations

Country	Name	City	State
United States	Bayview Medical Center	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Examine the T-cell Receptor Profile Changes Induced in the Tumor After SABR	T-cell receptor (TCR) profile changes in the tumor using TCR sequencing.	Baseline to up to 7 days after SABR treatment
Secondary	Evaluate Candidate Tumor Antigens Released From the Tumor by SABR	Candidate tumor antigens, mutation associated neo-antigens (MANAs), and tumor associated neo-antigens, (TAAs) released from the tumor by SABR	post-SABR
Secondary	Semiquantitative Scoring System to Describe the Influx of Key Tumor Infiltrating Lymphocytes in the Tumor After SABR.	Semiquantitative immunohistochemistry scoring system was used to evaluate pathological changes, immune-cell populations (CD8, FoxP3), within the tumor. Semiquantitative scoring system: 0 None, 1: 1-5, 2: 6-10, 3: 11-20, 4: 21 or more positive cells per high powered field (400x). Score for each participant is reported.	5 to 7 day post SABR
Secondary	Detection of Peripheral Neoantigen-specific T-cell Responses and Dynamics After SABR.	Assessed by the Mutation-Associated Neoantigen Functional Expansion of Specific T-cells (MANAFEST) assay. Number of participants where a peripheral neoantigen-specific T-cell responses and dynamics was detected is reported.	Within one year after SABR
Secondary	Dual-energy (DE) CT Imaging Characteristics After SABR	Dual-energy (DE) CT imaging characteristics after SABR. Evaluate relationship between dual-energy (DE) CT imaging characteristics, radiation dose, and early post-SABR pathologic outcomes after treatment with SABR.	1 year
Secondary	Number of Participants With Grade 2+ Toxicity Events	Patients with grade 2+ toxicity measured by NCIs Common Terminology Criteria for Adverse Events (CTCAE 4.0), due to post-SABR biopsy.	Pre-SABR, Post-SABR, 3, 6, 9 and 12 months.
Secondary	Semiquantitative Scoring System to Describe the Influx of Key Tumor Infiltrating Lymphocytes Within the Peritumoral Stoma After SABR.	Semiquantitative immunohistochemistry scoring system was used to evaluate pathological changes, (CD8, FoxP3, PD-L1/PD-1) expression within the peritumoral stoma after SABR. Semiquantitative scoring system: 0 None, 1: 1-5, 2: 6-10, 3: 11-20, 4: 21 or more positive cells per high powered field (400x). Score for each participant is reported.	5 to 7 day post SABR