Membrane-Bound IL15 TILs for Toxicity-Free Expansion
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current adoptive cell therapies using tumor-infiltrating lymphocytes (TILs) face challenges such as antigen loss, tumor microenvironment inhospitability, and toxicity associated with interleukin-2 (IL2) administration, leading to reduced efficacy and increased side effects.
Innovation Solution
Engineering TILs to express membrane-bound interleukin-15 (mbIL15) to enable expansion and activation without exogenous cytokines like IL2, using vectors like gamma-retroviral or lentiviral vectors, and linking mbIL15 to drug-responsive domains for regulated activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If exogenous interleukin-2 (IL2) is administered to expand and activate TILs, then TIL proliferation and anti-tumor activity are improved, but severe toxicity occurs including capillary leak syndrome, hypotension, and shock
Solution Approach 1:
The patent extracts the essential function of IL2 (T cell expansion and activation) and transfers it to a membrane-bound form expressed directly on the TIL surface. This eliminates the need for exogenous IL2 administration while maintaining the desired immunological effects, thereby resolving the contradiction between TIL expansion and toxicity.
Solution Approach 2:
The TILs are engineered to express mbIL15 on their own surface, allowing them to self-stimulate expansion and activation without requiring external cytokine administration. This self-service mechanism eliminates the harmful side effects of exogenous IL2 while maintaining therapeutic efficacy.
2Reliability
If high doses of IL2 are administered to achieve effective TIL therapy, then anti-tumor efficacy is improved, but life-threatening side effects increase
Solution Approach 1:
The patent extracts the therapeutic function of high-dose IL2 and implements it through endogenous mbIL15 expression on TILs. This localized cytokine production achieves effective anti-tumor activity without the systemic toxicity associated with high-dose exogenous IL2 administration.
Solution Approach 2:
The mbIL15 expressed on TIL surfaces acts as an intermediary that mediates T cell activation and expansion locally at the tumor site, replacing the need for systemic IL2 administration and its associated harmful effects.
3Quantity of substance
If TILs are expanded in vitro with exogenous cytokines, then cell numbers increase, but TIL exhaustion occurs reducing potency
Solution Approach 1:
The patent enables TILs to undergo expansion through self-stimulation via mbIL15 expression, eliminating the need for exogenous cytokine support during in vitro expansion. This self-driven expansion preserves TIL potency and prevents exhaustion while achieving adequate cell numbers for therapy.
4Reliability
If a single tumor antigen is targeted, then initial response may be achieved, but antigen loss and recurrence of aggressive clones occur
Solution Approach 1:
The patent employs TILs with diverse TCR clones that can recognize multiple tumor antigens simultaneously. The mbIL15 enhancement applies to this entire heterogeneous population, improving their overall functionality and ability to target multiple antigens, thereby preventing antigen loss and tumor recurrence.
Data Source
AI summary
Provided herein are tumor-infiltrating lymphocytes (TILs) engineered to express a membrane-bound interleukin 15 (mbIL15). The mbIL15 TILs can be expanded in vitro using a rapid expansion protocol without the use of exogenous interleukin 2 (IL2) and can be used in adoptive cell therapy without concomitant use of an exogenous cytokine such as IL2. The TIL can be further engineered such that the mbIL15 is operably linked to one or more drug responsive domains (DRDs), polypeptides that can regulate the abundance and/or activity of the IL15 upon binding of the DRD with a ligand. Also provided herein are components for making the modified TILs and methods for making and using the modified TILs.