How many FDA approved CAR-TILs are there?

Introduction to CAR-TIL Therapies
CAR-TIL therapies represent an emerging intersection between two promising immunotherapeutic strategies: chimeric antigen receptor (CAR) modification and tumor-infiltrating lymphocyte (TIL) therapy. Although both approaches harness the power of a patient’s immune cells to target cancer, CAR-TIL therapies are founded on the concept of combining the innate tumor-specific qualities of TILs with the enhanced specificity and signaling capability of engineered CARs. This hybrid strategy is garnering attention as a potential means to overcome some of the limitations encountered by both CAR-T cell therapies and conventional TIL treatments.

Definition and Mechanism of Action
Tumor-infiltrating lymphocytes (TILs) are immune cells that naturally migrate into the tumor microenvironment. They are thought to include subpopulations that can recognize and respond to tumor-specific antigens, though their activity is often suboptimal due to immune exhaustion or suppression in the hostile tumor niche. In contrast, CAR-T therapies involve harvesting peripheral blood T cells from patients, genetically modifying them in vitro to express chimeric antigen receptors that target specific tumor-associated antigens (such as CD19, BCMA, etc.), and then reinfusing these cells back into the patient. The CAR molecule confers an MHC-independent recognition mechanism, while also providing costimulatory and activation signals that drive T-cell proliferation and cytotoxicity.

CAR-TIL therapies thus aim to create a therapeutic cell product that leverages the naturally tumor-homing properties of TILs while also benefiting from the potent activation signals provided by CARs. When these engineered TILs encounter their target antigen within the tumor environment, the CAR domain can trigger robust signaling pathways leading to enhanced cell activation, proliferation, cytokine release, and sustained cytotoxicity. This dual mechanism is intended to overcome the limited persistence or efficacy of conventional TILs and may potentially address some of the challenges observed with standard CAR-T cells applied to solid tumors.

Differences between CAR-T and TIL Therapies
While both CAR-T and TIL therapies fall under the umbrella of adoptive cell transfer immunotherapies, several key differences define their development and clinical application:

• Source of Cells:
– Traditional CAR-T therapies typically use T cells harvested from peripheral blood, which are then engineered to express a CAR targeting a specific antigen.
– TIL therapies, on the other hand, involve the extraction of lymphocytes from within the tumor itself. These cells naturally exhibit tumor antigen specificity, but must often be expanded ex vivo to produce sufficient numbers for effective treatment.

• Antigen Recognition:
– CAR-T cells benefit from engineered receptors that enable MHC-independent recognition of target antigens, which can be ideal for hematological malignancies where antigens such as CD19 are well defined.
– TILs inherently recognize a broad array of tumor antigens, including neoantigens that arise from tumor-specific mutations. However, their specificity can be variable and may not always result in potent antitumor responses.

• Efficacy in Different Tumor Types:
– CAR-T therapies have demonstrated tremendous efficacy in blood cancers; however, their effectiveness in solid tumors is limited by factors such as tumor microenvironment immunosuppression.
– TIL therapies have shown promise in solid tumors (e.g., melanoma), but they often face hurdles with limited expansion and short persistence in vivo. CAR-TIL therapies aim to integrate the homing advantages and antigen breadth of TILs with the potent engineering of traditional CARs to generate a more effective therapeutic cell product for solid tumors.

FDA Approval Process

Overview of FDA Approval for Cellular Therapies
The U.S. Food and Drug Administration (FDA) oversees the approval of cellular therapies through rigorous evaluation of their safety, efficacy, quality, and manufacturing consistency. Over the past several years, multiple CAR-T cell therapies have received FDA approval for indications such as B-cell acute lymphoblastic leukemia (B-ALL), large B-cell lymphomas, and multiple myeloma. The approval process generally involves a series of clinical trials (from phase I through phase III) that establish the therapeutic benefit and identify potential risks, such as cytokine release syndrome (CRS) and neurotoxicity. Criteria addressed during the review include the mechanism of action, cell-manufacturing standards, clinical trial endpoints, and post-marketing safety monitoring.

For cellular therapies, the FDA expects comprehensive data to support the claim that the therapy leads to a clinically meaningful benefit which outweighs its risks, along with surmountable and manageable adverse events. Manufacturers must adhere to current good manufacturing practices (cGMP) and demonstrate robust and reproducible production processes, ensuring that each dose is consistent in terms of potency and purity as well as free of contaminants.

Specific Criteria for CAR-TIL Approval
In the context of CAR-TIL therapies, additional considerations would have to be met beyond those for conventional CAR-T products:

• Tumor Specificity and Safety:
Given that CAR-TILs combine aspects of TIL specificity with synthetic receptor design, it is imperative to establish that the engineered cells selectively target tumor cells without harming normal tissues. The risk for off-tumor toxicity must be minimized, and any potential for antigen escape should be thoroughly characterized in preclinical studies.

• Manufacturing Challenges:
CAR-TIL therapies inherently involve two critical processes: isolating TILs from tumor biopsies and then engineering these cells with a CAR construct. The FDA would require detailed process validation that both these components can be reliably performed in a clinical setting. The manufacturing process must be scalable and reproducible, especially when dealing with autologous cells, where variability between patients can be significant.

• Clinical Efficacy:
Clinical trial designs must clearly demonstrate that CAR-TIL therapy confers a significant benefit over existing treatment modalities. This includes robust demonstration of tumor response rates, durability of response, and overall survival benefits. Data from early-phase trials should ideally show that the hybrid feature of CAR-TILs results in superior infiltration, persistence, and antitumor activity compared to standard TIL therapy or traditional CAR-T cell products.

• Long-term Safety and Monitoring:
As with any novel cellular therapy, the FDA would anticipate long-term follow-up data on treated patients to monitor for delayed adverse effects and secondary malignancies. This is especially important given the potential for CAR-TIL therapies to include additional genetic modifications beyond the CAR expression, which may have implications for long-term genomic stability and safety.

Current FDA-Approved CAR-TIL Therapies

List and Details of Approved Therapies
After a detailed review of the reference materials from reliable sources, it is clear that the current landscape of FDA-approved cellular therapies includes several CAR-T cell products. However, it is critical to distinguish between conventional CAR-T cell therapies and CAR-TIL therapies.

• Conventional CAR-T Cell Therapies:
There are currently multiple FDA-approved CAR-T cell therapies for hematological malignancies. These include:
– Tisagenlecleucel (Kymriah®) for B-ALL and certain types of large B-cell lymphoma.
– Axicabtagene ciloleucel (Yescarta®) for relapsed or refractory B-cell lymphomas.
– Brexucabtagene autoleucel (Tecartus®) for mantle cell lymphoma.
– Lisocabtagene maraleucel (Breyanzi®) for large B-cell lymphoma.
– Idecabtagene vicleucel (Abecma®) and ciltacabtagene autoleucel (Carvykti®) for multiple myeloma.

• CAR-TIL Therapies:
Despite the extensive progress in adoptive cell transfer therapies, there are currently no FDA-approved CAR-TIL therapies. While TIL therapies exist as a treatment modality for solid tumors, they are generally not combined with CAR engineering in approved products. Instead, clinical trials evaluating CAR-TIL therapies are still exploratory in nature. CAR-TIL therapy is a promising avenue for enhancing the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma. However, this strategy has not yet advanced to the stage of FDA approval.

Thus, based on the current body of literature and reliable structured data, the number of FDA-approved CAR-TIL therapies is: zero (0). This conclusion is supported by the fact that all approved therapies to date are categorized under conventional CAR-T cell products, and although there is active research into CAR-TIL strategies, no such product has completed the regulatory pathway for approval.

Indications and Usage
For the FDA-approved conventional CAR-T cell products, the indications are specific to hematological malignancies, reflecting the robust clinical trial data and clear antigen targets in these diseases. For example:

• Tisagenlecleucel (Kymriah®):
Indicated for pediatric and young adult patients with relapsed/refractory B-ALL, and later for adult patients with certain large B-cell lymphomas.

• Axicabtagene ciloleucel (Yescarta®):
Approved for relapsed or refractory large B-cell lymphoma in adults.

• Brexucabtagene autoleucel (Tecartus®):
Indicated for mantle cell lymphoma.

• Lisocabtagene maraleucel (Breyanzi®):
Designed for use in large B-cell lymphomas.

• Idecabtagene vicleucel (Abecma®) and Ciltacabtagene autoleucel (Carvykti®):
Both approved for treating relapsed/refractory multiple myeloma.

In contrast, CAR-TIL therapies would be expected to broaden treatment options for solid tumors if and when they achieve regulatory approval. Their theoretical usage would leverage the natural propensity of TILs to infiltrate tumors combined with the engineered potency of CAR signaling. However, because no CAR-TIL therapy has met the FDA approval criteria, there is currently no indication or clinical usage for such a therapy in the approved setting.

Challenges and Future Directions

Current Challenges in CAR-TIL Development
The clinical development of CAR-TIL therapies encounters several challenges that have slowed their progression from experimental research to FDA approval:

• Manufacturing Complexity:
CAR-TIL production requires two sequential complex procedures—first isolating TILs from tumor biopsies and then engineering them with a CAR construct. Each step introduces variability and technical hurdles that are less prominent in peripheral blood–derived CAR-T cell therapies. Ensuring standardized, reproducible manufacturing processes is a significant challenge, especially given the intrinsic heterogeneity of TIL populations.

• Safety Concerns:
Combining CAR engineering with TIL characteristics may bear unforeseen risks. The additional genetic modifications could potentially lead to off-target effects or exacerbated cytokine release, especially if the engineered TILs home to normal tissues. Addressing safety issues such as cytokine release syndrome (CRS) and neurotoxicity, which are already concerns for conventional CAR-T products, will require robust preclinical safety data before FDA consideration.

• Efficacy and Persistence:
One of the primary motivations for developing CAR-TILs is to improve the durability and specificity of the antitumor response in solid tumors. However, achieving long-term T cell persistence, sufficient expansion, and robust antitumor activity in the immunosuppressive tumor microenvironment remains a major scientific hurdle. Many of these challenges are being addressed through novel CAR designs or combinatorial treatments, but the translation of these experimental therapies to successful clinical outcomes is still pending.

• Regulatory and Clinical Trial Challenges:
Due to their complexity, CAR-TIL therapies would likely face more stringent regulatory scrutiny compared to conventional CAR-T therapies. Regulatory guidelines would demand comprehensive data on the manufacturing process, cellular phenotype and heterogeneity, and long-term safety. Additionally, designing clinical trials that adequately demonstrate a clear benefit over existing therapies is a challenge that investigators are still working to overcome.

Future Prospects and Research Directions
Looking ahead, multiple research directions and innovative strategies are being pursued to overcome the current limitations of CAR-TIL development:

• Advanced CAR Designs:
Researchers are iterating on CAR design by incorporating dual-targeting domains, eliminating tonic signaling components, and adding safety switches to prevent uncontrolled T-cell activity. These improvements could potentially allow CAR-TILs to be used safely and effectively in the hostile tumor microenvironment of solid tumors.

• Enhanced Manufacturing Techniques:
Efforts to streamline and standardize the manufacturing process are critical. Innovations such as closed, automated systems for TIL expansion and CAR transduction have the potential to improve product consistency and reduce production times. This is essential for CAR-TIL therapies, where the starting material (tumor tissue) is inherently variable.

• Combination Therapies:
Combining CAR-TIL therapies with other immunomodulatory agents such as checkpoint inhibitors, cytokines, or targeted small molecules may enhance their antitumor efficacy. Such combination therapies could potentially overcome the immunosuppressive signals present within the tumor microenvironment, thereby boosting the persistence and activity of the infused cells.

• Biomarker Development:
Identification and validation of predictive biomarkers for response, persistence, and toxicity will be paramount. Robust biomarker assays can aid in patient selection and in monitoring the efficacy of the therapy during clinical trials. This data will not only assist in evaluating CAR-TIL products but also satisfy some of the regulatory requirements for long-term safety monitoring.

• Clinical Trials and Regulatory Pathways:
Early-phase clinical trials are currently exploring the feasibility of CAR-TIL therapies in various solid tumors, notably melanoma. Although these studies are in preliminary phases, they are crucial steps toward building the data required for eventual FDA approval. Collaborative efforts between academic centers, industry partners, and regulatory bodies will be essential for establishing standardized pathways for CAR-TIL development.

Conclusion
In summary, while the field of cellular immunotherapy has made significant advances with several FDA-approved CAR-T cell therapies for hematological malignancies, there remain no FDA-approved CAR-TIL products as of the current state of research. CAR-T cell therapies such as Tisagenlecleucel, Axicabtagene ciloleucel, Brexucabtagene autoleucel, Lisocabtagene maraleucel, Idecabtagene vicleucel, and Ciltacabtagene autoleucel have all received regulatory approval. These approvals reflect highly successful clinical trial data for blood cancers. In stark contrast, CAR-TIL therapies, which represent a hybrid approach intended to combine the tumor homing advantage of TILs with the potent and engineered signaling of CARs, have not reached the stage of FDA approval and remain purely investigational.

This outcome is due to several factors. First, the manufacturing process for CAR-TILs is exceptionally complex and variable, given the source material is derived directly from tumor tissues. Second, the dual nature of these cells—combining endogenous TIL properties with potentially potent CAR activation—poses unique safety challenges that have yet to be fully resolved. Third, while early-phase clinical data hint at promising antitumor efficacy and a potential future role for CAR-TILs, robust, reproducible, and scalable clinical trial results are still pending.

From a regulatory perspective, the FDA has rigorous criteria that require both safety and efficacy to be well-demonstrated. As of now, only conventional CAR-T therapies have satisfied these criteria, further underscoring that the number of FDA-approved CAR-TIL therapies is zero.

Overall, the innovative concept behind CAR-TIL therapies holds significant promise for the treatment of solid tumors—a domain in which traditional CAR-T strategies have met with limited success. Researchers continue to explore novel CAR designs, improved manufacturing protocols, and combination strategies to ultimately bring CAR-TILs to clinical fruition. Despite the current lack of FDA-approved products, the future of CAR-TIL therapy remains an active area of research with the potential to revolutionize cancer immunotherapy once its challenges are adequately addressed.

In conclusion, based on the structured and reliable data, there are currently NO FDA-approved CAR-TIL therapies. All FDA-approved products in this space pertain to conventional CAR-T cells designed for hematological malignancies, while CAR-TIL therapies continue to be a promising yet experimental approach under active investigation.