Engineered aAPCs for TIL Expansion Without Donor Variability

Solution Overview

Problem

Current methods for expanding tumor infiltrating lymphocytes (TILs) using artificial antigen presenting cells (aAPCs) face challenges such as poor performance, high variability, and reliance on allogeneic peripheral blood mononuclear cells (PBMCs), which are costly and logistically complex, and often result in unfavorable T cell phenotypic skewing.

Innovation Solution

Engineered myeloid lineage cells, including MOLM-13, MOLM-14, EM-3, and EM-2 cells, transduced with costimulatory molecules like CD86, 4-1BBL, and OX40L, are used to create aAPCs that efficiently expand TILs with minimal variability and without relying on human blood samples, allowing for consistent and high-yield TIL expansion.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If PBMCs are used as feeder cells for TIL expansion, then high expansion efficiency is achieved, but allogeneic variability, viral contamination risk, and logistical complexity increase

Engineering Contradiction:

ImproveTIL expansion efficiencyVSAvoiddonor cell quality consistency

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent creates artificial antigen-presenting cells (aAPCs) that copy the essential functions of allogeneic PBMCs without using actual human cells. The aAPCs express HLA molecules, costimulatory molecules (CD86, 4-1BBL, OX40L), and adhesion molecules to replicate the antigen presentation and T cell activation functions of PBMCs, thereby achieving TIL expansion without the variability and contamination risks of donor-derived cells

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The patent uses engineered cell lines (such as K562-derived aAPCs) that can be manufactured in vitro and used as disposable feeder cells. These aAPCs are produced from master cell banks, allowing consistent, scalable production without needing to collect, test, and cryopreserve human donor PBMCs for each TIL expansion batch

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

2Productivity

If PBMCs are used as feeder cells for TIL expansion, then high expansion efficiency is achieved, but cost and logistical complexity increase

Engineering Contradiction:

ImproveTIL expansion efficiencyVSAvoidcell product production simplicity

Core Design Contradiction:

ProductivityVSEase of manufacture

Solution Approach 1:

The patent creates artificial antigen-presenting cells (aAPCs) that copy the essential functions of allogeneic PBMCs without using actual human cells. The aAPCs express HLA molecules, costimulatory molecules (CD86, 4-1BBL, OX40L), and adhesion molecules to replicate the antigen presentation and T cell activation functions of PBMCs, thereby achieving TIL expansion without the variability and contamination risks of donor-derived cells

Inventive Principle:

Principle #26Copying

Solution Approach 2:

The patent uses engineered cell lines (such as K562-derived aAPCs) that can be manufactured in vitro and used as disposable feeder cells. These aAPCs are produced from master cell banks, allowing consistent, scalable production without needing to collect, test, and cryopreserve human donor PBMCs for each TIL expansion batch

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Adaptability or versatility

If conventional aAPCs are used for TIL expansion, then PBMC dependency is reduced, but expansion performance and consistency deteriorate

Engineering Contradiction:

ImproveaAPC independence from PBMCsVSAvoidTIL expansion performance

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent engineers aAPCs with specific localized molecular characteristics on their surfaces. The aAPCs are designed to express specific combinations of HLA class I and class II molecules, costimulatory molecules (CD86, 4-1BBL, OX40L), and adhesion molecules in defined ratios and patterns, creating optimal local interaction zones for T cell recognition and activation, thereby achieving both PBMC independence and high expansion performance

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates composite artificial antigen-presenting cells that combine multiple engineered components: HLA-transduced target cells, costimulatory molecule-expressing cells, and adhesion molecule-modified cells. These composite aAPCs integrate multiple functions that collectively replicate the complex interactions between allogeneic PBMCs and TILs, achieving superior expansion performance without donor cell variability

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS11667890B2Engineered artificial antigen presenting cells for tumor infiltrating lymphocyte expansion

Publication Date: 2023.06.06 IOVANCE BIOTHERAPEUTICS INC

AI summary

In some embodiments, compositions and methods relating to isolated artificial antigen presenting cells (aAPCs) are disclosed, including aAPCs comprising a myeloid cell transduced with one or more viral vectors, such as a MOLM-14 or a EM-3 myeloid cell, wherein the myeloid cell endogenously expresses HLA-AB/C, ICOS-L, and CD58, and wherein the one or more viral vectors comprise a nucleic acid encoding CD86 and a nucleic acid encoding 4-1BBL and/or OX40L and transduce the myeloid cell to express CD86 and 4-1BBL and/or OX40L proteins. In some embodiments, methods of expanding tumor infiltrating lymphocytes (TILs) with aAPCs and methods of treating cancers using TILs after expansion with aAPCs are also disclosed.