Lifileucel

Melanoma is a malignant neoplasm (abnormal tissue mass formed due to division activity in excess from one cell) of the melanocytes (cells in charge of producing skin colour)^[1]. Based on this, we can affirm that melanoma disease is a type of cancer. Much has been said and researched about the case of melanoma. However, the results of several investigations point to UV radiation (UVr) as the main trigger for this type of cancer^[1]. This radiation is believed to impact several key routes to developing this disease. The mechanism of the disease is often associated with mutations in the BRAFV600E gene due to UVr that will lead to cancer melanoma and, in most cases, to advanced metastasis ^[2]. According to cited literature, also other mutations in several genes can lead to the development of these abnormalities, such as NRAS, c-KIT and GNAQ/GNA11 gene mutations. Data obtained from melanoma tumours revealed that in approx. 50% of the mutations present in melanomas are related to BRAF. Demonstrating how this mechanism plays a critical role. What causes UVr into melanocytes is a substitution from C > T ^[3] , forming pyrimidine dimers in the DNA. BRAF genes are considered to be an oncogene in charge of encoding a protein kinase which promotes cell proliferation^[1]. The highly studied mechanism and the statistical relevance of the BRAF gene make this a suitable target for treating this disease. However, like many types of cancer, melanoma has also developed resistance to commonly used drugs and even shown resistance against new and novel immunological therapies such as immune checkpoint inhibitors (ICI). Because of this, patients with advanced melanoma or metastatic one do not have many alternatives ^[4]. In addition, data presented by Sarnaik et al. affirm that about 60% of patients using ICI will develop resistance to this, and between 35% to 40% will discontinue therapy because of treatment-emergent adverse events. Therefore, THERE ARE NOT TREATMENTS for patients with advanced melanoma after ICI therapy. Besides this tragic scenario, the treatment lifileucel/AMGTAVI has been proposed for treating patients in this type of situation. Lifileucel has as a target to enhance the immune response from the body receptor against melanoma cells^[5]. Therefore, lifileucel/AMGTAVI is not considered to be a protein or small molecule; instead, it is a novel cell therapy using tumour- infiltrating Lymphocytes (TIL) extracted from the patient’s tumour for ex vivo manipulation and then reintroducing again to the patient intravenously^[5].

Lifileucel, sold under the brand name Amtagvi, is an adoptive T cell therapy used for the treatment of melanoma.^[6][7][8]

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.^[8] 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.^[8] T cells are a type of cell that helps the immune system fight cancer and infections.^[8]

Lifileucel is the first tumor-derived T cell immunotherapy approved by the US Food and Drug Administration (FDA).^[8] It was approved for medical use in the United States in February 2024.^[7][9]

As mentioned above, 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^[10]. 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 ^[11] . 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^[12]

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 ^[12]. 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^[13].

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^[14]. Regarding the IL2 half-life, this cytokine has a very short one, with an average of 85 minutes for elimination and 13 minutes for distribution^[15] , 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) ^[16]. These pathways (metabolism) have been studied for many years in many mammals.

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).^[8]

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%)^[12] . 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 ^[12] . However, the less severe adverse effect with a high incidence (20%) includes symptoms like fever, rigors, hypotension, rash, chills, tachycardia, coughs and wheezing ^[12]. There is no evidence of an overdose to cause a toxicological effect.

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^[4]. 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 ^[16]. The supplementary information includes a table summarising the clinical trial (Phase II and III).

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.^[8] 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).^[8]

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.^[8]

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^[17]. 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.

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.

Lifileucel was approved for medical use in the United States in February 2024.^{[7][9][18][19]}

Lifileucel is the international nonproprietary name.^[20]

 This article incorporates public domain material from US Food and Drug Administration. United States Department of Health and Human Services.

• "Lifileucel". NCI Thesaurus.