# TIL therapy (tumor-infiltrating lymphocytes)

TIL therapy — autologous tumor-infiltrating T-cells with polyclonal specificity; the first approved drug Lifileucel (Amtagvi, Iovance, FDA 2024) is a breakthrough in metastatic melanoma.

Source: https://en.bioecon.ru/technology/til-therapy/
Updated: 2026-08-18



## Overview 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

| Level | Description | Key inputs/outputs |
|:---|:---|:---|
| **Tumor Resection** | surgical removal of the patient's tumor tissue | **In:** patient. **Out:** tumor tissue. |
| **TIL Isolation** | dissociation, TIL pool isolation (+/− CRISPR PD-1 KO) | **In:** tissue. **Out:** TIL pool. |
| **REP Expansion** | IL-2 + anti-CD3 expansion (14–22 days) | **In:** TIL pool. **Out:**10^9–10^{11}$ cells. |
| **QC & Cryostorage** | sterility, viability, phenotype; freezing | **In:** expanded TIL. **Out:** cryobanked product. |
| **Conditioning & Infusion** | patient lymphodepletion, TIL infusion + IL-2 | **In:** product, patient. **Out:** infused patient. |
| **Follow-up** | response and toxicity monitoring (CRS, ICANS) | **In:** patient. **Out:** therapy outcome. |

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.

---

## US

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.

---

## CN

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.

---

## EU

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.

---

## Leading companies and research institutes

| Company / Institute | Country | Key products / platforms | Tech features | Status 2026 |
|:---|:---|:---|:---|:---|
| **Iovance** | 🇺🇸 USA | *Lifileucel (Amtagvi)* | first approved TIL; iCTC plant | Commercial |
| **Instil Bio** | 🇺🇸 USA | TIL platforms | optimised expansion | Scaling |
| **MD Anderson** | 🇺🇸 USA | academic TIL | survival datasets | Research |
| **Memorial Sloan Kettering** | 🇺🇸 USA | CRISPR-TIL | PD-1/Cbl-b knockout | Research |
| **NKI** | 🇳🇱 Netherlands | academic TIL | Hospital Exemption | Research |
| **CCIT** | 🇩🇰 Denmark | academic TIL | decentralized production | Research |

---

## Tech 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.

---

## Value 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.