TCR CDR3 Clone Analysis for Adoptive Cell Therapy Clonality
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Solution Overview
Problem
Current methods for profiling T-cell receptors in cancer patients are ineffective in assessing clinical response to cancer therapies, particularly in adoptive cell therapies, as they produce vast data with unclear conclusions regarding T-cell diversity and its impact on clinical outcomes.
Innovation Solution
The method involves identifying and analyzing T cell receptor (TCR) complementarity determining region 3 (CDR3)-encoding nucleic acid sequence clones to determine clinically effective populations of tumor infiltrating lymphocytes (TILs) by comparing their diversity in therapeutic and peripheral blood mononuclear cells, sorting clones by frequency, and selecting the most prevalent ones.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If general T-cell receptor profiling methods are used in adoptive cell therapy, then vast data is produced, but the data provides no clear conclusions about T-cell diversity impact on clinical response
Solution Approach 1:
The patent extracts and focuses specifically on TCR CDR3 beta nucleic acid sequences from the complex T-cell receptor data. By isolating this particular region that encodes the antigen-binding site, the method filters out irrelevant information while retaining the clinically meaningful signals about T-cell diversity and therapeutic response
Solution Approach 2:
The patent changes the measurement parameter from general T-cell receptor profiling to specific CDR3 beta sequence frequency analysis. This parameter transformation converts the vast, inconclusive data into focused measurements of clonal diversity that directly correlate with clinical response to adoptive cell therapy
2Measurement precision
If comprehensive TCR profiling is performed on therapeutic TILs and PBMCs, then clonal diversity is measured, but identifying clinically effective populations remains difficult
Solution Approach 1:
The patent transforms the complex population identification problem into a simpler frequency comparison task by measuring CDR3 beta sequence frequencies in both therapeutic TILs and post-infusion PBMCs. This parameter change reduces the complexity from identifying effective populations directly to comparing sequence frequency distributions
Solution Approach 2:
The patent uses the presence of CDR3 beta sequences in post-infusion PBMCs as feedback to identify which TIL clones persisted and were clinically effective. This feedback mechanism allows retrospective identification of effective populations based on their detectable presence in the patient's circulation after therapy
Data Source
AI summary
Methods and systems for identifying clinically effective population of tumor infiltrating lymphocytes are disclosed. Also disclosed are methods for identifying persistent unique clones derived from adoptive cell therapy products.