# Lifileucel

Lifileucel, sold under the brand name Amtagvi, is an adoptive T cell therapy used for the treatment of melanoma.
Specifically, lifileucel is a tumor-derived T cell immunotherapy composed of a recipient's own T cells. A portion of the recipient's tumor tissue is removed during a surgical procedure prior to treatment. The recipient's T cells (the tumor-infiltrating lymphocytes) are separated from the tumor tissue, multiplied and then infused into the patient in a single dose. T cells are a type of cell that helps the immune system fight cancer and infections.
Lifileucel is the first tumor-derived T cell immunotherapy approved by the US Food and Drug Administration (FDA). It was approved for medical use in the United States in February 2024.

## Medical uses

Lifileucel is indicated for the treatment of adults with unresectable (unable to be removed with surgery) or metastatic (spread to other parts of the body) melanoma previously treated with other therapies (a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor).

## Side effects

There are many side effects and toxicological aspects to consider before administering this therapy. The manufacturer mentions that there is a correlation between death and treatment (7.5%). The deaths are because of side effects such as severe infections (26.9%), internal organ bleeding, acute renal failure, bone marrow failure and many other organism failures. This can be within a period of 30 days to 150 days. Likewise, different reactions can occur after the first day of infusion; the most common is the hypersensitivity reaction. However, the less severe adverse effect with a high incidence (20%) includes symptoms like fever, rigors, hypotension, rash, chills, tachycardia, coughs and wheezing There is no evidence of an overdose to cause a toxicological effect.

## Pharmacokinetics

Before using the TIL in the patient, this must go under chemotherapy to suppress the immunological system. After this, AMTAGVI is administrated intravenously with a dose 7.5 X 109 to 72 X 109 viable cells with a frequency of just one time. The therapy will reach its target, as any lymphocyte would do to trigger the immunological system, so the delivery of the active treatment will be through the blood. A critical step for the administration and correct functioning of AMTAGVI is the application of Interleukin-2 (IL2) after the AMTAGVI infusion. This is because IL-2 will help to promote and enhance the activity of dendritic cells, which are in charge of antigen presentation, CD8+ and T cell activity.
This information can be used to discuss bioavailability. However, the manufacturer or other databases have yet to publish this data, and the same is true for half-life. Nevertheless, as AMTAGVI is administered intravenously, we can consider 100% bioavailability (as mentioned above) and a regular immunology activity disposition because AMTAGVI therapy is a mix of IL-2 and cytotoxic T cells. Using literature as a base, the half-life of CD4+ and CD8+ is 87 and 77 days, respectively. Regarding the IL2 half-life, this cytokine has a very short one, with an average of 85 minutes for elimination and 13 minutes for distributio,n but enough to trigger a proper immune response.
Because of the nature of this therapy, metabolism and elimination are from an immunological perspective. After a T cell encounters its specific antigen, there are many pathways that a lymphocyte can follow in an immune response. The most common and principal mechanisms are apoptosis (via intrinsic, extrinsic, or caspase pathways), activated cell-autonomous death (ACAD), and activation- induced cell death (AICD). These pathways (metabolism) have been studied for many years in many mammals.

## Melanoma background

Melanoma is a malignant neoplasm (abnormal tissue mass formed due to excessive division of a single cell) of melanocytes, the cells responsible for producing skin pigment. As such, melanoma is classified as a type of cancer.

### Causes and mechanisms

Extensive research has identified ultraviolet radiation (UVr) as the primary environmental trigger for melanoma. UVr is believed to initiate multiple pathways leading to the disease, primarily through genetic mutations. A key mutation linked to melanoma is V600E in the BRAF gene, which promotes cancer development and, in most cases, leads to metastasis. Other genetic mutations associated with melanoma include NRAS, c-KIT, and GNAQ/GNA11.
Genomic analysis of melanoma tumors has revealed that approximately 50% of cases involve BRAF mutations, highlighting the critical role of this mechanism. UVr exposure causes C > T substitutions in melanocyte DNA, leading to the formation of pyrimidine dimers. The BRAF gene, classified as an oncogene, encodes a protein kinase that drives cell proliferation. Due to its well-studied role and statistical significance, the BRAF pathway is a major target for melanoma therapies.

### Treatment challenges and resistance

Despite therapeutic advances, melanoma has shown resistance to many conventional treatments, including targeted drugs and immunotherapies such as immune checkpoint inhibitors (ICI). Patients with advanced or metastatic melanoma often have limited treatment options. Studies indicate that about 60% of patients receiving ICI therapy develop resistanc, and 35%–40% discontinue treatment due to severe adverse effects.

### Emerging therapies: Lifileucel

Given the high resistance rates, new treatment approaches are being developed. One promising therapy is lifileucel (AMTAGVI), a tumor-infiltrating lymphocyte (TIL) therapy designed to enhance the immune system’s ability to target melanoma cells. Unlike traditional small-molecule drugs or protein-based therapies, lifileucel is a form of cell therapy. It involves extracting TILs from the patient’s tumor, modifying them ex vivo, and reinfusing them into the patient to boost the immune response against melanoma.
The main advantage of this cell therapy is that it offers a possible treatment for a better quality of life after all melanoma-related treatments have failed. It is incredible to understand how specific innovative therapies, such as the immune checkpoints (Nobel prize winners), have failed. However, it is even more amazing to know how new innovative therapies such as AMTAGVI/Lifileucel can tackle this situation. When a small molecule or a biologic doesn’t work, we can achieve health and safety through other ways, such as Cell therapy and gene therapy, among others. Unfortunately, many disadvantages are related to this treatment. Since people who are candidates for this treatment have endured many health problems, taking the risk of AMGTAGVI may be even more painful.

## Chemistry

AMTAGVI is a tumour autologous T cell immunotherapy (biologic), and nowadays, there are not many patients for this therapy because it’s the last resource for treating melanoma. Due to this, an industrial process doesn ́t exist. However, Iovance Biotherapeutics, Inc (the manufacturer) describes the manufacturing process from “tumour to treatment process” as follows: AMTAGVI starts with tumour tissue collection by surgery; after this, the tissue collected is shipped to a high-level laboratory (not specified) and T cell are extracted. These, are amplified and grow to a billion-scale for shipping back to the treatment centre where the patient is located Although the procedure to expand the lymphocytes is not described by the manufacturer, the TIL expansion methodology has been well-defined in other sources, and a method proposed by the Karolinska Institutet has been used as a base for this article With this, the formulation of the AMTAGVI is composed of CD4+, CD8+, monocytes, B cells and NK cells (but mostly the two first).
The formula contains 48% PlasmaLyte A, 50% CryoStor CS10, 2% of 25% human serum albumin, and 300 IU/mL IL-2 (61). Finally, AMTAGVI is delivered in bags containing 125 mL of viable cells

## History

The safety and effectiveness of lifileucel was evaluated in a global, multicenter, multicohort, clinical study including adult participants with unresectable or metastatic melanoma who had previously been treated with at least one systemic therapy, including a PD-1 blocking antibody, and if positive for the BRAF V600 mutation, a BRAF inhibitor or BRAF inhibitor with an MEK inhibitor. Effectiveness was measured via the objective response rate to treatment and duration of response (measured from the date of confirmed initial objective response to the date of progression, death from any cause, starting a new anti-cancer treatment or discontinuation from follow-up, whichever came first).
The US Food and Drug Administration (FDA) approved Lifileucel through the accelerated approval pathway and granted the application orphan drug, regenerative medicine advanced therapy, fast track, and priority review designations under the brand name Amtagvi to Iovance Biotherapeutics.
The clinical trials for lifileucel/AMGTAVI in melanoma include two phases. Phase II (178 patients) demonstrated the therapy’s efficacy and durable response in patients with unresectable or metastatic melanoma who had failed PD-1 blockers and BRAF inhibitors. However, adverse effects were statistically significant. Phase III (670 patients) aims to compare lifileucel combined with pembrolizumab for advanced melanoma stages (IIIC, IIID, or IV). Results are expected by 2028 and full completion by 2030. The supplementary information includes a table summarising the clinical trial (Phase II and III).

## Society and culture
### Legal status

Lifileucel was approved for medical use in the United States in February 2024.

### Names

Lifileucel is the international nonproprietary name.

### IPR/Marketing

Regarding patents, many TIL therapies exist under different brands and for many cancer types. However, according to DrugBank, there are no patents registered to AMGTAVI, but some FDA protocols are protected. The leading cause of these could be patent protection, especially for the type of medium used for the growth of lymphocytes after tumour tissue extraction and some other formulations. Related to the generic version of AMTAGVI, the possibility of a generic treatment is almost null because of the highly personalised therapy offered. There is a possibility of similar treatments for other types of cancer, but they will not be a generic version of AMTAGVI.
According to the Pharmaceutical Technology portal, AMTAGVI will generate an annual revenue of 584,000 million dollars in the USA. Currently, AMTAGVI is only available in the USA. However, it ́s expected to expand to other regions in the future to increase its market share. When this report was written, AMTAGVI/Lifileucel was the first and only cellular therapy for melanoma treatment. For instance, no competitors or other existing drugs are available in the market.