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Immune cell therapy

Table of contents

Reading time 20 minutes

Updated - February 21, 2026

The immune system - what does it do?

The immune system maintains a whole army of scouts, fighters (T-cells) and helpers. They constantly patrol the body and search for intruders such as bacteria, viruses, but also the body's own cells that have gone wild - cancer cells.

Normally, such rampaging cells are quickly detected by the guardians of the immune system, killed and their remains removed and decomposed. This happens continuously every day. In this way, most cancer cells are prevented from spreading by the immune system and are rendered harmless in good time.

But cancer cells are inventive, as they want to survive at all costs. So they disguise themselves, hide effectively from the guardians of the immune system and continue to spread almost unchallenged. Not only do they make themselves unrecognizable as the enemy, they also keep the immune system so busy that after a certain time it becomes exhausted and may even have to stretch its wings - and succumb to the cancer.

What immune cell therapy does

In immune cell therapy, immune cells are removed from the patient, equipped with e.g. better recognition technology, more fighting power or a new „target optic“ and returned to the body, where they can attack and destroy the cancer in a more targeted manner.

The genius of it

Unlike chemotherapy, which in principle kills everything that divides quickly (cancer cells on the one hand, but also - unintentionally - hair cells, intestinal cells, etc.), immune cell therapies target only on cancer cells - at least in theory.

As the immune system remembers enemies it has recognized, it immediately attacks the new cancer cells and destroys them should the cancer return. This explains why some patients remain permanently tumor-free after a single infusion.

The three types - very simple

1. CAR-T cells: The conversion
T-cells (the immune system's combat troops) are taken and a completely new „gripper arm“, an artificial receptor, is built into them in the laboratory. This recognizes a very specific feature on the surface of the cancer cell and then destroys the cancer cell directly.

2 TCR T cells: The better glasses
Similar to CAR-T, instead of an artificial grasping arm, the T cell is given an improved natural receptor that also recognizes characteristics that are deeply inside of the cancer cell and only tiny fragments show to the outside.

3rd TIL therapy: The veteran
Here, T cells are taken that are already in the tumor itself and know him. They are extracted, multiplied en masse in the laboratory - a few cells become billions - and sent back to experienced „veterans“.

T cells and their role

The adaptive immune system is based on two main cell types: B cells (antibody production) and T-cells (cellular immunity). T cells, which are divided into two functional populations, are primarily relevant for all immune cell therapies:

CD8+ cytotoxic T cells (CTL)
Recognize peptide-MHC class I complexes on the surface of infected or malignant cells via their T-cell receptor (TCR) and induce their apoptosis through perforin/granzyme B release or FasL/Fas interaction.

CD4+ helper T cells
Coordinate the immune response via cytokine secretion (IL-2, IFN-γ, TNF-α) and are essential for the long-term persistence of the CTL response.

Scientific basis:

Tumor immunology basic principle

Cancer does not develop in an immunological vacuum. The Cancer Immunoediting-concept (Dunn, Bruce & Schreiber, 2004) describes three phases:

Elimination
The immune system recognizes and destroys transformed cells via tumor-associated antigens (TAA) and tumor-specific antigens (TSA). MHC-I-mediated presentation of mutant peptides activates CTL.

Equilibrium
The immune system keeps tumor growth in balance, but at the same time selects for immune-resistant variants.

Escape
Cancer cells escape through downregulation of MHC-I, overexpression of immune checkpoints (PD-L1, CTLA-4 ligands), secretion of immunosuppressive cytokines (TGF-β, IL-10) and recruitment of regulatory T cells (Tregs).

Scientific basis:

CAR-T cell therapy - design and mechanism

Molecular structure of the CAR

A chimeric antigen receptor (CAR) is a synthetic transmembrane protein with four functional domains:

1. extracellular binding domain
Mostly a scFv (single-chain variable fragment) of a monoclonal antibody. Binds directly to a surface antigen (e.g. CD19 on B cells, BCMA on plasma cells) in an MHC-independent manner. This MHC-independence is a fundamental difference to the natural TCR.

2. hinge/linker region
Flexible spacer between binding domain and cell membrane (e.g. IgG4-Hinge, CD8α-Hinge). Length and flexibility strongly influence the binding efficiency.

3. transmembrane domain
Anchors the CAR in the T cell membrane; influences signal stability.

4. intracellular signaling domain
Consists of primary activation domain (CD3ζ with 3 ITAMs) + co-stimulatory domains. The co-stimulatory domains define the CAR generation:

GenerationCo-stimulationFeature
1st genCD3ζ onlyShort-lived, weak proliferation
2nd genCD28 or 4-1BB (CD137) + CD3ζStandard today; Kymriah=4-1BB; Yescarta=CD28
3rd genCD28 and 4-1BB + CD3ζStronger activation, increased risk of CRS
4th gen2nd gene + transgene (e.g. IL-12, IL-15)„Armored CAR“, improved tumor microenvironment
5th gen2nd gene + intracellular IL-2Rβ domainJagged-CAR; JAK-STAT signaling pathway

4-1BB vs. CD28 co-stimulation
4-1BB-CARs (Kymriah) show better long-term persistence and less exhaustion (less T-cell exhaustion), CD28-CARs (Yescarta) show faster initial activation and higher early response rates, but tend to have a shorter response duration.

Scientific basis:

Manufacturing process (Autolog)

Leukapheresis
The collection of mononuclear blood cells from the patient's blood via cell separation over 3-5 hours.

T-cell activation
Ex vivo stimulation with anti-CD3/anti-CD28 antibody-coated beads or recombinant ligands; addition of IL-2 and IL-7/IL-15 to promote proliferation.

Gene transfer
Introduction of the CAR gene by means of:

  • Lentiviral vector (Kymriah, Breyanzi): Stable integration into the host genome; long-term expression
  • Gammaretroviral vector (Yescarta, Tecartus): Similar, but higher insertional mutagenesis risk
  • Transposon systems / mRNA (experimental): Non-integrating alternatives

Expansion
Multiplication of the transduced cells over 7-14 days to typically 10⁸-10⁹ cells.

Quality control
Check for CAR transduction efficiency, sterility, residual components, T-cell phenotype, potency test.

Cryopreservation & transportation
to the treatment center.

Lymphodepletion
Patient receives chemotherapy (usually fludarabine + cyclophosphamide) 2-7 days before CAR-T infusion to reduce the body's own immune cells and create „space“ (lymphodepletive conditioning). This step massively increases the proliferation and persistence of CAR-T cells via homeostatic IL-7/IL-15 signals.

Infusion
Single intravenous infusion of CAR-T cells.

The science behind it:

Mechanism of action & effector phase

After infusion, CAR-T cells recognize their target antigen on tumour cells, whereby an immunological synapse is formed: The CAR binds the antigen → CD3ζ-ITAMs are phosphorylated → ZAP-70/Lck kinase cascade → NF-κB, NFAT, AP-1 activation → perforin/granzyme B release (direct cytolysis) + IFN-γ, TNF-α (cytokine secretion).

Parallel: Bystander activation - released cytokines activate other endogenous immune cells and can lead to cytokine release syndrome (CRS).

Science:

TCR-T cell therapy: the key differences

Why TCR and not CAR for intracellular antigens?

CAR receptors only recognize Surface proteins. However, since most tumor-specific antigens are localized intracellularly (transcription factors, metabolic enzymes, cancer testis antigens such as PRAME, MAGE-A4), CAR-T would be blind to these targets.

The natural TCR has the ability to recognize intracellular proteins, as cellular proteins are constantly recognized by the Proteasome are degraded to ~8-11 amino acid long peptides. These peptides are degraded in the endoplasmic reticulum to MHC class I molecules (HLA in humans) and transported to the cell surface. There they are bound by the αβ-TCR, a mechanism that is active on all nucleated body cells.

The technical challenge of TCR therapy is the necessary HLA restriction: a natural high-affinity TCR only recognizes a specific peptide in the context of a specific HLA allele (e.g. HLA-A*02:01, which occurs in approx. 40-50 % of the Caucasian population). This means that patients must be both HLA-compatible and tumor-positive for the target antigen.

Structure of the therapeutic TCR

Therapeutic TCRs are mostly αβ-TCR heterodimers, which:

  • Developed through phage display or mouse humanization with extremely high affinity (KD in the pM range). The natural TCR has only medium affinity (μM), as too high affinity would lead to autoimmunity
  • Stabilized against unintended pairing with endogenous TCR chains by murine substitutions or disulfide bridges
  • be introduced into the patient's own T cells via lentiviral transduction

Science:

TIL therapy - principle of natural tumor detection

Biological basis

Tumors are infiltrated by immune cells, the tumor-infiltrating lymphocytes (TIL). These T cells have already recognized the tumour, but are often exhausted, anergic or too few due to the immunosuppressive tumour microenvironment (TME). High TIL density in the tumor correlates with a better prognosis in many types of cancer.

The idea of TIL therapy (developed by Steven Rosenberg at the NCI, Bethesda, in the 1980s): Take these already tumor-specific T cells, free them from the immunosuppressive environment, activate and multiply them massively ex vivo, and return them in such large numbers that they become therapeutically effective despite a tendency to exhaustion.

Manufacturing process (Lifileucel)

Tumor excision
At least 1.5 cm³ of tumor tissue is surgically removed and immediately processed into Iovance Biotherapeutics, Inc. sent.

Initial expansion (approx. 11 days)
Tumor is mechanically and enzymatically dissociated; TIL are cultivated in the presence of IL-2 → Pre-REP (Pre-Rapid Expansion Protocol).

Rapid Expansion (approx. 11 days)
TILs are treated with anti-CD3 antibodies (OKT3), irradiated allogeneic PBMCs (which act as antigen-presenting cells) and IL-2 on >7.5 × 10⁹ cells expands (from a few million to billions).

Lymphodepletion & infusion
Identical to CAR-T: Flu/Cy conditioning, then single TIL infusion, followed by IL-2 administration for further in vivo expansion.

Time frame
Approx. 22 days production; total from tumor removal to infusion approx. 6-7 weeks.

Science:

Challenges - current research approaches

Antigen escape

Problem definition
Tumor cells can downregulate or lose expression of the target antigen. In CD19-CAR-T, CD19-negative relapse occurs in 30-40 % of cases.

Solution
Dual targeting strategies (CD19+CD22, BCMA+CD38), tandem CARs, logic gate CARs (AND gate: require two antigens; NOT gate: only kill cells without protective antigen).

T-cell exhaustion (exhaustion)

Problem definition
Tumor cells can downregulate or lose expression of the target antigen. In CD19-CAR-T, CD19-negative relapse occurs in 30-40 % of cases.

Chronic antigen exposure → Expression of exhaustion markers (PD-1, TIM-3, LAG-3, TOX transcription factor) → Loss of function.

Solution: Combination with checkpoint inhibitors, epigenetic reprogramming via TET2 knockdown, next-gen CAR designs with built-in checkpoint blockade.

Tumor microenvironment (TME)

Problem definition
Tumor cells can downregulate or lose expression of the target antigen. In CD19-CAR-T, CD19-negative relapse occurs in 30-40 % of cases.

Solid tumors have a hostile microenvironment: hypoxia, glucose deficiency, immunosuppressive cytokines (TGF-β, IL-10), Tregs, MDSCs.

Solution
Armored CARs with IL-12/IL-15/IL-18 secretion, PD-1-resistant CARs, combination with anti-VEGF, local intratumoral injections.

Cytokine storm (CRS) & ICANS

Problem definition
CRS is caused by massive cytokine release (IL-6, IFN-γ, IL-1β) of activated CAR-T and macrophages. Severe CRS (grade 3-4) requires intensive therapy. ICANS (neurological toxicity) results from endothelial activation and blood-brain barrier dysfunction.

Management
Tocilizumab (IL-6R blockade), corticosteroids, anakinra (IL-1 blockade); early intervention improves results.

Allogeneic „off-the-shelf“ therapies

Problem definition
Tumor cells can downregulate or lose expression of the target antigen. In CD19-CAR-T, CD19-negative relapse occurs in 30-40 % of cases.

Autologous production takes 3-6 weeks and is expensive (400,000-600,000 €).

Solution
Allogeneic CAR-T from healthy donors, with CRISPR knockout of endogenous TCR (GvHD prevention) and HLA components (rejection prevention).

Current data
CTX112 (CRISPR-allogeneic CD19-CAR-T) shows first complete remissions in CLL in phase 1.

2.7 Quantitative effectiveness data at a glance

TherapyIndicationORRCR rateMedian OSsource
TisagenlecleucelB-ALL pediatric81 %60 %NR (63 % at 12 mo)NEJM 2018
Axicabtagene-celDLBCL 3rd line83 %58 %NR (74 % at 12 mo)NEJM 2017
Ciltacabtagene-celMult. myeloma98 %78 %NR (>80 % at 12 mo)Lancet 2021
LifileucelMelanoma31,4 %7,5 %NR (49 % at 24 mo)JCO 2022
Afamitresgene-celSynovial sarcoma43 %4 %16.4 monthsLancet 2024
TebentafuspUveal melanoma9 % (ORR)<1 %21.7 monthsNEJM 2021

(NR = Not Reached; OS* not yet reached)

*O.S (Overall Survival ) - e.g. „median OS 21.7„ that half of the patients had died after 21.7 months and the other half were still alive

Further reading & resources

Reviews:

Guidelines & databases:

Patient-friendly resources (German):

In less than a decade, immune cell therapy has made the leap from experimental concept to standard clinical therapy - with the number of approved products and indications continuing to grow rapidly. For patients who are eligible, it may be the only potentially curative option.

Globally approved immune cell therapies

Status 02.2026

Introduction: The three major classes

Today, the term „immune cell therapy“ covers three different product categories in the oncological context:

1. CAR-T cell therapy (Chimeric Antigen Receptor T-Cells)
Genetically modified T cells with a synthetic surface receptor that recognizes tumour antigens on the cell surface. All products approved to date are directed against CD19 or BCMA and are approved for blood cancers.

2. TCR-T cell therapy (T-Cell Receptor T-Cells)
Genetically modified T cells with an optimized natural T cell receptor that recognizes intracellular tumour proteins presented on the HLA complex. First approved for solid tumors in 2024.

3rd TIL therapy (Tumor-Infiltrating Lymphocytes)
Non-genetically modified T cells obtained from the patient's tumor, massively multiplied and reinfused. First approved for melanoma in 2024.

As of December 2024, the FDA had approved six CAR-T cell therapies, with ten CAR-T cell therapies commercially available worldwide. In addition, there is a TIL therapy (Lifileucel) and a TCR therapy (Afamitresgene autoleucel) - the first in their class for solid tumors. MRA

CAR-T CELL THERAPIES

Tisagenlecleucel (Kymriah®) - Novartis

Target antigen: CD19
Approved: FDA 2017 / EMA 2018
First CAR-T product ever approved worldwide

Indications

  • Children & young adults up to 25 years: relapsed/refractory B-cell ALL (acute lymphoblastic leukemia)
  • Adults: relapsed/refractory large B-cell lymphoma (LBCL) after ≥2 systemic therapies
  • Relapsed/refractory follicular lymphoma (FL)

Most important studies

Regulatory authorities

  • FDA
  • EMA
  • TGA (Australia)
  • PMDA (Japan)

Manufacturer/Website: Novartis Kymriah

FDA product page: FDA Kymriah

Axicabtagene Ciloleucel (Yescarta®) - Kite/Gilead

Target antigen: CD19
Approved: FDA October 2017 / EMA August 2018

Indications

  • Large B-cell lymphoma (DLBCL, PMBCL, HGBCL, tFL) after ≥2 systemic therapies
  • Primary refractory DLBCL or relapse within 12 months (2nd line)
  • Relapsed/refractory follicular lymphoma after ≥2 systemic therapies

Most important studies

Treatment centers (D/A/CH selection)

All qualified FACT/JACIE-accredited transplant centers; in Germany e.g. University Medical Center Hamburg-Eppendorf, Charité Berlin, LMU Klinikum München, University Medical Center Heidelberg.

Manufacturer/Website: Gilead Yescarta

Brexucabtagene Autoleucel (Tecartus®) - Kite/Gilead

Target antigen: CD19
Approved: FDA July 2020 (MCL), October 2021 (ALL adult) / EMA December 2020

Indications

  • Relapsed/refractory mantle cell lymphoma (MCL) after BTK inhibitor
  • Adults with relapsed/refractory B-cell ALL

Most important studies

FDA product page: FDA Tecartus

Lisocabtagene Maraleucel (Breyanzi®) - Bristol Myers Squibb

Target antigen: CD19
Approved: FDA February 2021 (initial) / extended indications 2022-2024 / EMA October 2022

Indications

  • Large B-cell lymphoma (LBCL, DLBCL, HGBCL, FL) 2nd + 3rd lineage
  • Chronic lymphocytic leukemia (CLL) / small cell lymphocytic lymphoma (SLL) after ≥2 therapies incl. BTK inhibitor (FDA 2024)
  • Follicular lymphoma (FL) after ≥2 systemic therapies

Most important studies

FDA product page: FDA Breyanzi

Idecabtagene Vicleucel (Abecma®) - Bristol Myers Squibb / 2seventy bio

Target antigen: BCMA (B-cell maturation antigen)
Approved: FDA March 2021 / EMA August 2021

Indication

  • Relapsed/refractory multiple myeloma after ≥4 previous lines of therapy

Most important study

FDA product page: FDA Abecma

Ciltacabtagene Autoleucel (Carvykti®) - Janssen/Legend Biotech

Target antigen: BCMA (dual-binding)
Approved: FDA February 2022 (≥4 lines), extended April 2024 (≥1 line) / EMA May 2022

Special feature: Unique dual-antibody CAR with two BCMA-binding single-domain antibodies; considered the most effective approved myeloma therapy to date

Indications

  • Relapsed/refractory multiple myeloma after ≥4 lines of therapy
  • Since April 2024 (FDA): after ≥1 line of therapy for lenalidomide-refractory disease

Most important studies

FDA product page: FDA Carvykti
Manufacturer: carvykti.com

Obecabtagene Autoleucel (Aucatzyl®) - Autolus (new: 11.2024)

Target antigen: CD19 (fast-off-rate design - lower toxicity than predecessor)
Approved: FDA November 8, 2024

Indication

  • Adults with relapsed/refractory B-cell ALL

Special feature: First CAR-T product approved without REMS (Risk Evaluation and Mitigation Strategy) program; a sign of improved safety and a novel CD19 binding concept.
The yellow sheet

Most important study

  • FELIX study (phase 1/2, CR rate 42 % in 3 months): NCT04404660

FDA product page: FDA Aucatzyl
Manufacturer: autolus.com

ALLOWED WORLDWIDE - NOT IN USA/EU (other countries)

China (NMPA) - four additional CAR-T products

A total of eleven autologous CAR-T cell therapies have received initial approval worldwide. Seven by the FDA and four by the Chinese NMPA, all for relapsed/refractory hematologic malignancies.
Immatics US, Inc.

Trade nameActive ingredientTarget antigenIndicationAuthorization
CarteyvaRelmacabtagene autoleucelBCMAMult. Myeloma, DLBCLNMPA 2021/2023
FucasoEquecabtagene autoleucelBCMAMult. myelomaNMPA 2023
YuanruidaSatricabtagene autoleucelCD19B-cell lymphomaNMPA
Zever-cel—CD19/BCMAHematolog.NMPA
CarvyktiCiltacabtagene autoleucelBCMAMult. myelomaNMPA 2024

India (CDSCO)

NexCAR19 (Actalycabtagene autoleucel) was approved in October 2023 as the first CAR-T therapy developed in India. Developed by ImmunoACT at IIT Bombay, the therapy costs around USD 50,000 - around a tenth of comparable Western products. The yellow sheet

Indication

  • Relapsed/refractory B-cell non-Hodgkin's lymphoma and B-cell ALL

Treatment center: Tata Memorial Hospital, Mumbai
Manufacturer: ImmunoACT

TCR-T CELL THERAPIES (approved)

Afamitresgene Autoleucel (Tecelra®) - Adaptimmune (August 2024)

On August 2, 2024, the FDA approved Afamitresgene autoleucel (Afami-cel, Tecelra) as the first ever TCR T-cell therapy for the treatment of cancer and specifically the first genetically engineered T-cell product for a solid tumor. PubMed Central

Target antigen: MAGE-A4 (intracellular cancer testis antigen), presented by HLA-A*02:01
Approved: FDA August 2024

Indication

  • Adults with unresectable or metastatic cancer Synovial sarcoma (soft tissue sarcoma), pre-treated with chemotherapy, MAGE-A4-positive and HLA-A*02:01-positive

In the pivotal Phase 2 SPEARHEAD-1 trial, the tumors of synovial sarcoma patients responded to treatment for a median of 11.6 months. In some patients, no tumor could be detected for several years. Clinicaltrialvanguard

Most important study

Treatment center (Pioneer): Memorial Sloan Kettering Cancer Center, New York - MSK Tecelra Info
FDA product page: FDA Tecelra
NCI article: cancer.gov TCR therapy

Tebentafusp-tebn (Kimmtrak®) - Immunocore (January 2022)

Not a classical cell product (not an infused T-cell product), but a bispecific TCR fusion protein, but mechanistically in the category of TCR-based immunotherapy and often discussed as a precursor of the PRAME-TCER® technology.

Mechanism: Binds on one side to gp100 peptide+HLA-A*02:01 on tumor cells, on the other to CD3 on T cells (ImmTAC technology).
Approved: FDA January 2022 / EMA February 2022

Indication:

  • HLA-A*02:01-positive adults with unresectable or metastatic cancer uveal melanoma (ocular melanoma) - 1st line

Special feature: First drug ever approved for uveal melanoma

In the phase 3 IMCgp100-202 study, tebentafusp showed a significant survival advantage over physician's choice (pembrolizumab, ipilimumab or dacarbazine): median OS 21.7 vs. 16.0 months (HR 0.51; p<0.0001). The 1-year OS rate was 73 % vs. 59 %. Kitz-heidelberg

Most important study

FDA page: fda.gov Kimmtrak
Manufacturer: immunocore.com/kimmtrak

TIL-THERAPY (approved)

Lifileucel (Amtagvi®) - Iovance Biotherapeutics (February 2024)

Lifileucel was approved on February 16, 2024 as the first ever T-cell therapy for a solid tumor and the first TIL therapy in history. Immatics N.V.

Mechanism: Tumor is surgically removed, tumor-infiltrating lymphocytes (TIL) are isolated, massively multiplied and reinfused after lymphodepletion. No genetic modification - the natural tumor recognition of the TIL is used.

Indication

  • Adults with unresectable or metastatic cancer Melanoma (cutaneous melanoma) after prior anti-PD-1 therapy and BRAF/MEK inhibitor (if BRAF-mutated)

In the 5-year follow-up of the Phase 2 C-144-01 study, Lifileucel demonstrated an objective response rate of 31.4 % and a median duration of response of 36.5 months - with sustained long-term responses in over 30 % responders. Esmo

Most important study

Treatment centers (USA selection): Johns Hopkins, UCLA, MD Anderson, UCSF, Memorial Sloan Kettering, Mayo Clinic
NCI article: cancer.gov TIL therapy
Manufacturer: iovance.com
FDA product page: FDA Amtagvi

Overview of all immune cell therapies worldwide

ProductActive ingredientTypeGoalIndicationAuthorizationYear
KymriahTisagenlecleucelCAR-TCD19B-ALL pediatric, LBCL, FLFDA, EMA2017
YescartaAxicabtagene-celCAR-TCD19DLBCL, PMBCL, FL, tFLFDA, EMA2017
TecartusBrexucabtagene-celCAR-TCD19MCL, adult B-ALLFDA, EMA2020
BreyanziLisocabtagene-celCAR-TCD19LBCL, CLL/SLL, FLFDA, EMA2021
AbecmaIdecabtagene-celCAR-TBCMAMult. Myeloma ≥4 linesFDA, EMA2021
CarvyktiCiltacabtagene-celCAR-TBCMAMult. Myeloma ≥1 lineFDA, EMA, NMPA2022
KimmtrakTebentafusp-tebnTCR-Bispecificgp100+HLAUveal melanomaFDA, EMA2022
NexCAR19Actalycabtagene-celCAR-TCD19B-ALL, NHLCDSCO (India)2023
AmtagviLifileucelTILPolyclonalMelanoma (solid tumor)FDA2024
TecelraAfamitresgene-celTCR-TMAGE-A4+HLASynovial sarcomaFDA2024
AucatzylObecabtagene-celCAR-TCD19Adult B-ALLFDA2024

Side effects - what all therapies have in common

The most important common risks:

Cytokine storm (CRS)
Occurs frequently with CAR-T and TCR-T; rarely with TIL.
Treatment with tocilizumab.
Since 2024 on all CAR-T labels: Boxed warning for secondary T-cell malignancies (very rare, ~3.6 % within years).

ICANS (Neurotoxicity)
Immune cell-associated neurotoxicity syndrome; known in CAR-T, less common in TIL.

Cytopenias
The necessary lymphodepletion (chemotherapy before infusion) always results in short-term blood count changes.

Where are these therapies offered in Germany?

All FDA/EMA-approved CAR-T products are manufactured in specialized transplant centers certified by the manufacturers and accredited by DKMS/EBMT:

Complete list of certified CAR-T centers: EBMT Center Search

Outlook: What's next?

The next wave of approved immune cell therapies is expected to come in 2026-2028:

  • IMA203 / Anzu-cel (PRAME-TCR): Phase 3 SUPRAME trial underway - Possible approval for melanoma 2027/2028
  • Lifileucel + pembrolizumab (Phase 3): First-line study NCT05727904 - Possible first-line approval for melanoma
  • Brenetafusp (PRISM-MEL-301): Phase 3 study PRAME×CD3-Bispecific - Possible approval 2027
  • CAR-T for autoimmune diseases (SLE, MS): Phase 2 trials underway; potentially first non-oncology CAR-T product
  • KiTZ Heidelberg pediatric PRAME study: planned for 2026 - first study for children worldwide

SHI reimbursement of immune cell therapies in Germany

Status 02.2026

The situation is complex and varies greatly depending on the type of therapy, product and health insurance provider. There is no blanket, automatic reimbursement as there is for traditional medicines. Instead, there is a multi-stage system with a considerable amount of bureaucracy, which doctors and clinics openly criticize as dysfunctional.

CAR-T cell therapies

Generally refundable, but complicated

AMNOG & NUB procedure

CAR-T preparations are Advanced therapy medicinal products (ATMP) and are subject to the German AMNOG procedure (Pharmaceutical Market Reorganization Act). This provides for

Early benefit assessment by the G-BA

Since January 1, 2011, the G-BA has had the statutory task of conducting a benefit assessment for all newly approved medicinal products with new active substances immediately after market entry.
It is tested whether the new drug is superior to the previous standard therapy - the so-called appropriate comparator therapy - offers an advantage.

Legal basis: § Section 35a SGB V - Evaluation of the benefit of medicinal products (legal wording)

Procedure description G-BA: g-ba.de - AMNOG benefit assessment according to § 35a SGB V

The result of this benefit assessment is the starting point for the price negotiations between the GKV-Spitzenverband and the pharmaceutical manufacturer.
The possible categories for the assessment of added benefit are defined in the German Drug Benefit Assessment Ordinance and in Chapter 5 of the G-BA's Code of Procedure.

The four categories of additional benefit are:

  • Significant Additional benefits
  • Considerable Additional benefits
  • Lower Additional benefits
  • None Proven additional benefit

The four categories in the original wording: g-ba.de - Categories of added value

Legal basis of the categories: AM-NutzenV § 5 para. 7 - Drug Benefit Assessment Ordinance (legal wording)

Specific example: G-BA procedure for Yescarta (CAR-T): g-ba.de - Benefit assessment procedure Axicabtagene-Ciloleucel

All ongoing and completed G-BA assessment procedures: g-ba.de - Evaluation procedure overview

Price negotiation according to § 130b SGB V

On the basis of the G-BA's decision on the additional benefit of the new drug, the GKV-Spitzenverband and the pharmaceutical company usually negotiate the so-called reimbursement amount in four negotiation meetings within six months. This applies from the seventh month after market launch as the new nationwide dispensing price - for those with statutory health insurance, private insurance and self-payers alike.

Legal basis: § Section 130b SGB V - Agreements on reimbursement amounts (wording of the law)

Procedure description GKV-Spitzenverband: gkv-spitzenverband.de - AMNOG negotiations according to § 130b SGB V

Overview of all negotiated reimbursement amounts (incl. CAR-T products): gkv-spitzenverband.de - Reimbursement amount agreements

NUB procedure for hospitals

As CAR-T therapies are administered on an inpatient basis, the clinics are also subject to the NUB procedure (New examination and treatment methods in accordance with Section 6 (2) KHEntgG).

The NUB procedure closes the so-called „innovation gap“, the period of usually three years until a new therapy is fully incorporated into the G-DRG flat rate system.
During this period, hospitals can negotiate hospital-specific NUB fees with the health insurance funds, provided that the Institute for the Hospital Remuneration System (InEK) awards status 1 following a review.

Hospitals must submit NUB applications to InEK by October 31 each year. InEK publishes the results of its review by the end of January of the following year.

For ATMPs (advanced therapy medicinal products) - which include all CAR-T and TCR-T products - an extended application deadline of April 30 of each year applies, unless the application has already been submitted by October 31.

NUB procedure officially (InEK): g-drg.de - NUB procedure for ATMPs

NUB procedure (GKV-Spitzenverband): gkv-spitzenverband.de - NUB in hospitals

Detailed process explanation with ATMP special regulation: reimbursement.institute - NUB request procedure

AOK overview NUB 2025 (with current status figures): aok.de/gp - NUB in somatics

The reality: individual applications and bureaucracy

Despite negotiated reimbursement amounts, the practice for clinics and patients is considerably more complicated than the formal regulations would suggest.

Until now, the centers have generally had to submit an individual application for cost coverage by statutory health insurance.
There is no standardized, automatic cost coverage for people with statutory health insurance.

Source: DKFZ Cancer Information Service - Update CAR-T: Individual application procedure and discount agreements

As a CAR-T product costs several hundred thousand euros, clinics have to obtain cost coverage before they can start the therapy. Senior physician Dr. Veit Bücklein from LMU Klinikum München describes the effort involved: „We have to fill out a checklist and collect many, many documents, from A for doctor's letter to Z for compilation of all findings.“ The official procedure is called the „individual cost reimbursement application procedure“.

Source: Pharma facts - CAR-T: Promise of the future versus bureaucracy monster (LMU Klinikum München, September 2024)

Prof. Dr. Marion Subklewe, head of the CAR-T program at LMU Klinikum München, sums up the criticism: „We work with approved products. I don't understand why I have to submit an individual application for an approved product every time.“ The reimbursement processes are currently „an instrument to make progress more difficult“.

Source: Pharma facts - CAR-T: Optimal care looks different (April 2025)

Prof. Dr. Michael Hallek, Director of Clinic I for Internal Medicine at the University Hospital of Cologne, proposes the solution of systematically assigning CAR-T cell therapies to specialized centers that can document their work and demonstrate proven success, and then giving these centers a free hand in treatment decisions: „Then you can forget about the review process, because who else but us is supposed to judge whether a treatment is right or not?“

Source: Pharma facts - CAR-T: What is still missing (Event University Hospital Cologne, July 2025)

From the university hospitals' point of view, the core structural problem is that the legislator has not closed the time gap between the approval of a drug and the hospitals' guaranteed entitlement to reimbursement. In the case of new cell and gene therapies, the financial risk for hospitals is too high for them to be able to make advance payments.

Source: Uniklinika.de - CAR-T cell therapy: demand for reimbursement security

The medical consequences of these delays are measurable: a one-month wait for CAR-T cell therapy can increase relative mortality by 6.2 percent. Any delay in access to CAR-T can have a direct impact on the success of treatment.

Source: Pharma-Fakten / IQVIA Institute - CAR-T: Optimal care looks different (with reference to IQVIA study)

In addition, there is another structural problem: over 160 hospitals have submitted NUB applications to be able to offer CAR-T therapies - but initially only received NUB status 4, which means that the SHI is not obliged to cover the costs as part of NUB agreements.

Source: VDEK - Revolution in oncology: NUB status and reimbursement issues for CAR-T

Prof. Subklewe describes a particularly absurd individual example from everyday hospital life: „I have to be told that a gastroenterologist has to be nearby 24 hours a day, even though I've never needed one in the last five years.“
While certain quality and structural requirements make sense, they should not be allowed to get out of hand as they are at present.

Source: Pharma facts - CAR-T: Promise of the future versus bureaucracy monster

Overview of qualified CAR-T centers in Germany (for patients and referring physicians):

The „pay-for-outcome“ model

(performance-related reimbursement)

As an innovative interim solution, individual health insurance funds have developed so-called Pay-for-performance contracts closed:

Novartis and GWQ ServicePlus have concluded a success-oriented reimbursement model for Kymriah, the first agreement of its kind in Germany:
Novartis will reimburse part of the drug costs if the patient dies of blood cancer within a defined period after treatment.
The outcome parameter is the survival of the treated patient.

This model has set a precedent: Techniker Krankenkasse and other substitute health insurance funds have followed suit with similar agreements.

Which CAR-T products are eligible for reimbursement in Germany?

ProductIndicationSHI status
Kymriah (Tisagenlecleucel)B-ALL pediatric, DLBCL, FL✅ Refund amount negotiated (since Sept. 2019)
Yescarta (Axicabtagene-cel)DLBCL, PMBCL, FL, tFL✅ Refund amount negotiated
Tecartus (Brexucabtagene-cel)MCL, adult B-ALL✅ EMA-approved; NUB procedure ongoing/completed
Breyanzi (Lisocabtagene-cel)DLBCL, CLL, FLEMA-approved; NUB procedure
Abecma (Idecabtagene-cel)Multiple myelomaEMA-approved; NUB procedure
Carvykti (Ciltacabtagene-cel)Multiple myelomaEMA-approved; NUB procedure

Practical requirement in any case
The treating center must

  • fulfill the ATMP quality assurance guideline of the G-BA
  • FACT/JACIE accredited
  • and be certified as a CAR-T center.

Only then can NUB fees be agreed and billed.

Kimmtrak (Tebentafusp) - special case

Kimmtrak is not a cell product, but a Biopharmaceutical and is subject to the regular AMNOG procedure like other cancer drugs. It is administered on an outpatient basis and is generally reimbursable via the usual oncology billing pathways, but only for the approved indication (HLA-A*02:01-positive uveal melanoma, first line).

TIL therapy (Lifileucel / Amtagvi) - Currently NOT reimbursable in Germany

This is the most important current difference compared to the USA.

The company Iovance withdrew its application for approval from the EMA on July 22, 2025.

The EMA had concerns about the response rate in the main study as well as serious safety concerns, in some cases the therapy was associated with deaths.
In addition, the manufacturer lacked sufficient GMP documentation. American Society of Clinical Oncology

Iovance is currently developing a new strategy together with the EMA to obtain EU approval for Amtagvi. For the UK, approval is expected in the first half of 2026; Australia has granted Priority Review. GlobeNewswire

Conclusion for Germany: Lifileucel is currently available in the EU Not approved and not reimbursable. Patients who want this therapy must currently receive it in the USA, at their own expense or as part of clinical trials.

TCR-T therapies (Afami-cel / Tecelra) - Not approved in Europe

Afamitresgene autoleucel (Tecelra) is currently only approved in the USA (FDA, August 2024). An EMA application has not yet been submitted.

The following therefore applies to Germany: no reimbursement, no regular access, only via clinical studies or individual treatment trials (as in the case of Mailo at the KiTZ Heidelberg).

What to do if the health insurance company refuses? Legal options

If a statutory health insurer refuses to cover the costs of an EMA-approved therapy, the following options are available:

Objection (§ 78 SGB V)

  • Submit an objection in writing within 4 weeks of rejection.
  • The clinic and doctor should enclose a detailed medical report.

Social court action

  • If the decision is still negative, file a complaint with the competent social court.
  • In the case of life-threatening illnesses, a interim legal protection can be applied for,
    the court can provisionally order the assumption of costs.

§ Section 2 (1a) SGB V (Nikolaus resolution)

In the case of life-threatening illnesses and a lack of standard therapy, insured persons are entitled to a non-standard approved therapy if there is a serious prospect of a cure or noticeable relief. This is the central legal instrument for cases such as individual treatment attempts.

Important resources:

Austria

Austria: CAR-T cell therapy was included in the LKF service catalog in Austria on January 1, 2020 (group MEL22.30: „Administration of modified cells“) - thus regulated earlier and more clearly than in Germany. Clinicaltrialvanguard

Switzerland

Switzerland: Reimbursement via the KVG (Health Insurance Act) after inclusion in the FOPH's list of specialties; for EMA-approved CAR-T products possible in principle, also with individual case assessment.

Summary

TherapyEU approvalSHI reimbursement Germany
CAR-T (Kymriah, Yescarta, Tecartus, Breyanzi, Abecma, Carvykti)Yes (EMA)Basically yes - but via individual case application/NUB, with considerable bureaucracy
Kimmtrak (Tebentafusp)Yes (EMA)Yes (AMNOG procedure, outpatient)
Lifileucel / Amtagvi (TIL)No (EMA application withdrawn July 2025)No
Afami-cel / Tecelra (TCR-T)No (FDA only)No
PRAME-TCR (IMA203, experimental)No (Phase 3)No - only via study participation

The central political problem remains: To date, there is no really good legal and financing framework for quickly and reliably reflecting these innovative therapies in the German system. It can take years before a medical innovation is correctly reflected in the flat rate per case system.

PKV and immune cell therapy - The complete legal situation

Status: February 2026

The legal foundation: § 192 VVG and MB/KK 2009

In the case of medical expenses insurance, the insurer is obliged to reimburse the expenses for medically necessary treatment due to illness or the consequences of an accident to the extent agreed. The insurer is not obliged to pay benefits if the expenses for medical treatment or other benefits are conspicuously disproportionate to the benefits provided.

Legal wording § 192 VVG (complete): dejure.org - Section 192 VVG Typical contractual benefits of the insurer

Official sample conditions MB/KK 2009 (PDF, PKV-Verband): pkv.de - MB/KK 2009 sample conditions

The benefit obligations of private health insurers are essentially determined by the tariff selected in the individual case and the associated tariff conditions. According to § 192 Para. 1 VVG in conjunction with the MB/KK, expenses for medically necessary treatment due to illness or the consequences of an accident are reimbursed.

Explanation of the PKV benefit obligation according to § 192 VVG: legal-plus.eu - The PKV's obligation to pay: When and for what does the PKV have to pay?

The key term: „Medically necessary treatment“

According to established case law and in accordance with the model conditions MB/KK and § 192 VVG, medical necessity exists if the treatment is suitable, according to objective medical findings and knowledge, to recognize an illness, cure it, prevent its worsening or alleviate symptoms. The decisive factor is whether, in the opinion of a competent doctor at the time of treatment, the measure appears necessary according to recognized scientific standards.

Legal analysis: Definition of medical necessity in private health insurance: kanzlei-neue-kraeme.de - Reimbursement of cost-intensive treatment measures under private health insurance

In addition to treatments recognized by conventional medicine, private health insurance also reimburses treatments that have proven equally promising in practice or for which there is no alternative. These can also be new drugs or innovative diagnostic procedures and treatment methods that are considered useful by experts.

PKV Association: Official explanation of benefits and reimbursement (incl. innovative therapies): pkv.de - Benefits and reimbursement in private health insurance

The landmark judgment: OLG Frankfurt, 29.06.2022 - Ref. 7 U 140/21

This is the central ruling for the reimbursement of immune cell therapies by private health insurers in Germany.

Facts of the case
A patient had been diagnosed with a non-operable pancreatic tumor. After chemotherapy failed, he decided against standard palliative therapy, which offered a lower prognosis of success, and instead opted for dendritic cell therapy. He wanted to claim the costs from his private health insurance company, but it refused to pay in full.

Verdict
Dendritic cell therapy is a medical treatment within the meaning of the medical cost conditions (MB/KK 2009) of private health insurance companies. If a conventional first-line therapy does not lead to the desired treatment success for a person suffering from a life-destroying and incurable tumor, the insured person does not have to be referred to a second-line therapy with an even lower prognosis of effectiveness. Rather, they can demand direct payment of the costs of a new, scientifically sound alternative therapy if, at the time of treatment, this offers a not entirely remote prospect of achieving success beyond that of standard palliative therapy.

Full discussion of the judgment (DATEV Magazin): datev-magazin.de - OLG Frankfurt: PKV must bear costs of dendritic cell therapy

Judgment review with confirmation of legal force (January 2023): transkript.de - Health insurance company must pay for cell therapy (incl. confirmation of legal force)

Judgment analysis for hospitals (IWW Vergütungsrecht): iww.de - PKV must bear the costs of alternative therapy

Haufe: Brief summary of the judgment: haufe.de - Inoperable tumor: Alternative therapy covered by PKV

Detailed analysis of the judgment (Jöhnke & Reichow Rechtsanwälte): joehnke-reichow.de - Reimbursement of costs for dendritic cell treatment, OLG Frankfurt

Legal force: According to the Hessian Higher Regional Court, the deadline for filing an appeal has expired, meaning that the decision has been legally binding since January 2023.

The „conspicuous disproportion“ pursuant to Section 192 (2) VVG - and why it does not apply to CAR-T

The burden of presentation and proof for the existence of a conspicuous disproportion lies with the insurer. There is agreement that the usual value of the service provided is decisive and not the price for the medical minimum. Applying the case law of the Federal Court of Justice on usury offenses, a market comparison is a suitable means of determining the objective value.

Since CAR-T therapies are priced at a comparable level worldwide (€ 250,000-600,000), a „conspicuous imbalance“ can be invalidated by an international market comparison.

Legal analysis of the „conspicuous disproportion“ according to § 192 para. 2 VVG: kunzrechtsanwaelte.de - On the conspicuous disproportion within the meaning of Section 192 (2) VVG

The preliminary enquiry procedure in accordance with Section 192 (8) VVG - the most important practical step

As soon as it is foreseeable that the expected treatment costs will exceed €2,000, insured persons are entitled to information about the cost approval in accordance with Section 192 (8) VVG. The insurance company must confirm or reject the assumption of costs within 4 weeks of submission of the cost estimate.

If the information is not provided within the deadline, it is assumed by the insurer that the intended medical treatment is necessary until the contrary is proven. This Fiction of necessity for failure to respond is an important protective instrument for patients.

Wording of the law § 192 para. 8 VVG (obligation to make an inquiry in advance): dejure.org - Section 192 (8) VVG

Practical instructions: Preliminary inquiry with the PKV before cost-intensive treatment: pkv-inhalte.de - PKV insurance and expensive treatment: What's the right approach?

Legal consequences of incorrect or missing PKV information: versicherungsrechtsiegen.de - Cost commitment and § 192 para. 8 VVG in practice

In case of rejection: appeal and legal action

The question of reimbursement is determined by the interaction of § 192 VVG, the model conditions MB/KK and the individual tariff clauses. The decisive factor is whether treatment was carried out due to illness and whether it was medically necessary.

In the event of rejection by the PKV, the following options are available:

Objection with complete medical dossier (medical opinion, tumor board protocol, international study situation, cost estimate)

Action before the civil court (not social court, that is the difference to statutory health insurance) with application for interim injunction in case of urgent need for treatment

Complete guide: Contesting a PKV refusal, objection and legal action: kanzlei-neue-kraeme.de - Reimbursement of cost-intensive treatments under private health insurance

Refusal of private health insurance and benefits: legal steps at a glance: kva-plus.de - Rejection of cost coverage by private health insurance and state aid

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