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.