Pathologic and Immunologic Response After Ablative Radiation in Lung Cancer

• ClinicalTrials.gov Identifier: NCT03603002
• Recruitment Status: Recruiting
• First Posted: July 27, 2018
• Last Update Posted: November 24, 2021
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Non-small Cell Lung Cancer Stage I	Diagnostic Test: Post-SABR Biopsy	Not Applicable

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: 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.
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: Studying the Pathologic and Immunologic Response After Ablative Radiation in Stage I Non-Small Cell Lung Cancer
• Actual Study Start Date: October 16, 2018
• Estimated Primary Completion Date: August 2022
• Estimated Study Completion Date: August 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Stage I NSCLC with SABR Therapy; Participants receive stereotactic ablative radiotherapy (SABR) and pre-SABR biopsy as part of standard of care and then receive a post-SABR biopsy after receiving SABR.	Diagnostic Test: Post-SABR Biopsy; Post-SABR Biopsy

Outcome Measures

Primary Outcome Measures :

1. Induced T-cell receptor (TCR) profile changes in tumor after stereotactic ablative radiotherapy (SABR) as determined by number of times increase in amount of identified TCR CDR3 regions. [ Time Frame: Baseline to up to 7 days after SABR treatment ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Ranh Voong, MD; 4105506597; kvoong1@jhmi.edu

Contact: Beverly Lee, RN; 4105020874; blee55@jhmi.edu

Locations

United States, Maryland

Bayview Medical Center; Recruiting

Baltimore, Maryland, United States, 21224

Contact: Ranh Voong 410-550-6597 kvoong1@jhmi.edu

Contact: Beverly Lee 4105020874 blee55@jhmi.edu

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Investigators

• Principal Investigator: Khinh Ranh Voong, MD; Johns Hopkins University

More Information

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT03603002
• Other Study ID Numbers: J1826; IRB00163415 ( Other Identifier: JHM IRB )
• First Posted: July 27, 2018
• Last Update Posted: November 24, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms