TIL therapy (tumor-infiltrating lymphocytes)

01Overview and value chain

Markers: [EC: ATMP Regulation (EC No 1394/2007) | OECD: Bio-Pharmaceuticals | Regulator: FDA (USA), EMA (EU), NMPA (China)]

TIL therapy (Tumor-Infiltrating Lymphocytes) isolates, expands and re-infuses autologous T-cells that have deeply infiltrated a tumor. Unlike CAR-T (one surface antigen), TILs recognise a broad spectrum of a tumor’s personal neoantigens (polyclonal specificity) — minimising immune escape. The first approved drug in the class is Lifileucel (Amtagvi, Iovance), FDA-approved in early 2024 for metastatic melanoma after checkpoint inhibitors. A course costs about $515,000; the expansion phase (REP) is compressed from 22 to14 days in optimised protocols.

Key platforms of TIL therapy:

1. Standard TIL (Standard TIL): a polyclonal pool from dissociated tumor.
2. CRISPR-TIL (Genome-edited TIL): PD-1 or Cbl-b knockout for resistance to immunosuppression.
3. Repertoire expansion (REP): rapid expansion with IL-2 + anti-CD3 (REP phase).
4. Closed systems (Closed Systems): CliniMACS Prodigy for automated GMP manufacture.

Sectoral value chain

[tumor resection] ──> [dissociation + TIL isolation] ──> [REP phase (IL-2 + anti-CD3)]
                                                              │
                                                  (cryopreservation / QC)
                                                              │
                                                              ▼
[patient after lymphodepletion] <─── [TIL infusion] <─── [autologous product release]

Value chain levels

Cross-cutting technologies of the sector:

• CRISPR-TIL: PD-1/Cbl-b knockout to overcome the immunosuppressive microenvironment.
• Closed systems: CliniMACS Prodigy — automated sterile manufacture.
• Decentralised manufacture: Hospital Exemption (EU) — in-hospital production.

02US

The US leads: first global TIL approval (Lifileucel/Amtagvi, FDA 2024) and industrial infrastructure.

Iovance Amtagvi, iCTC mega-plant, Medicare coverage

• Iovance: Lifileucel (Amtagvi) — the first approved TIL drug; iCTC mega-plant (Philadelphia) for thousands of patients.
• MD Anderson / MSK: the largest long-term-survival clinical datasets.
• Medicare/Medicaid: TIL covered under dedicated DRG codes at a course cost of ~$515,000.

03CN

China is rapidly building clinical TIL experience in solid tumors.

National TIL protocols, fast REP, MOST funding

• Compressed REP: domestic protocols cut REP from 22 to14 days.
• Solid tumors: clinical activity in lung and cervical cancer.
• China MOST: subsidies for national TIL protocols.

04EU

The EU classifies TIL as ATMP; strict EMA oversight + academic programs.

EMA ATMP oversight, NKI/CCIT academic programs, Hospital Exemption

• EMA ATMP: REP-phase sterility in closed systems (CliniMACS Prodigy).
• NKI (Netherlands) / CCIT (Denmark): academic TIL programs at cancer institutes.
• Hospital Exemption: decentralized hospital production lowers cost.

05Leading companies and research institutes

06Tech stack and innovations

The stack rests on REP expansion, CRISPR modification and closed GMP systems.

1. REP expansion (Rapid Expansion):
   • IL-2 + anti-CD3 over 14–22 days to10^9–10^{11}$ cells.
2. CRISPR-TIL:
   • PD-1 or Cbl-b knockout for resistance to tumor immunosuppression.
3. Closed systems:
   • CliniMACS Prodigy — automated sterile manufacture under EMA ATMP.

07Value chains and production pipelines

Autologous TIL product manufacturing pipeline (ATMP / cGMP)

┌───────────────────────────┐      ┌───────────────────────────┐
│ 1. Tumor resection        │ ───> │ 2. TIL isolation (+CRISPR)│
└───────────────────────────┘      └───────────────────────────┘
                                                 │
                                                 ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 4. QC & cryopreservation  │ <─── │ 3. REP expansion (IL-2)   │
└───────────────────────────┘      └───────────────────────────┘
              │
              ▼
┌───────────────────────────┐      ┌───────────────────────────┐
│ 5. Patient lymphodepletion│ ───> │ 6. TIL infusion + IL-2    │
└───────────────────────────┘      └───────────────────────────┘

Stage 1: Tumor resection

Surgical removal of the tumor tissue from the autologous TIL donor patient.

Stage 2: TIL isolation

Tumor dissociation, TIL pool isolation; optionally CRISPR PD-1/Cbl-b knockout.

Stage 3: REP expansion

Expansion with IL-2 and anti-CD3 over 14–22 days to10^9–10^{11}$ cells.

Stage 4: QC & cryopreservation

Sterility, viability, phenotype; product frozen until infusion.

Stage 5: Lymphodepletion

The patient undergoes lymphodepletion (chemotherapy) to make a “niche” for the TILs.

Stage 6: Infusion

Intravenous infusion of autologous TILs with IL-2 support; CRS/response monitoring.