Blog | 5/8/2024
Navigating the Frontier of Tumor-Infiltrating Lymphocyte Therapy: Opportunities and Challenges
By Matthew Chin, Meghan Lu, Earl Gillespie, PhD, Ned Wydysh, PhD, and Vivek Mittal, PhD
Tumor-infiltrating lymphocytes (TILs) are the adaptive immune system’s frontline soldiers against cancer. While most TIL therapies are still in early stages of development, they have demonstrated significant promise for patients with solid tumors, with Iovance’s AMTAGVI achieving the first FDA approval for the class (Figure 1). Unlike their extratumoral counterparts, TILs possess inherent capabilities to recognize multiple unique targets from a patient’s tumor, allowing for highly individualized treatment. However, they are expected to face many of the same challenges experienced by other cell therapies, such as unwieldy logistics of patient cell harvesting and a costly manufacturing process.
What is TIL Therapy?
The TIL therapy process begins when TILs are isolated from a patient’s resected tumor tissue. The cells with the highest tumor recognition are selected and then expanded using IL-2 to form the infusion product (Figure 2). As with other cell-based interventions, the patient undergoes lymphodepletion before getting reinfused with the TILs to deplete regulatory T cells and promote TIL persistence [1]. As an autologous treatment derived from the patient’s tumor, TIL therapy mitigates the risk of rejection and better recognizes patient-specific tumor biomarkers, enabling robust and durable anti-tumor activity even in treatment-refractory cases. TIL therapies are sometimes likened to CAR-T therapies because both harness the power of the immune system to fight cancer, but the two differ in process, types of cancers they are effective against, and toxicity. CAR-T therapy engineers cells with specific antigen receptors, while TIL selection obviates the need for genetic modification. CAR-T therapy is predominantly effective in blood cancers such as leukemia, lymphoma, and multiple myeloma, whereas TIL therapy has demonstrated efficacy in solid tumors such as melanoma and non-small cell lung cancer (NSCLC) [2]. Furthermore, TIL therapy’s innate tumor specificity results in lower off-target toxicity.
Despite its advantages, TIL therapy has several limitations. First, it is limited to treating hot tumors where there is an immune response present within the tumor. Second, like with existing cell therapies, the TIL manufacturing process is cumbersome, time-consuming, and costly. Patients must be willing and able to perform an operation to extract tumor tissue, wait 4-6 weeks before treatment, and then undergo an inpatient hospital stay to receive treatment. The long wait could impede adoption, but this hurdle may shrink over time. CAR-T therapy manufacturing was also lengthy early on but has gotten more efficient, leading to its growing adoption: on average, CAR-T adoption exceeds 50% of its peak penetration after 5 years and reaches 100% peak penetration after 10 years [3]. Hopefully, the recent regulatory success of AMTAGVI will similarly spur TIL improvement and adoption by prompting further investment in manufacturing infrastructure. Improvements such as streamlining coordination between clinical and manufacturing teams and developing a standard protocol for harvesting and expanding TILs will be critical to reducing production times [4]. Finally, like with CAR-T therapies, high prices may pose additional accessibility challenges for many patients. AMTAGVI is currently priced at a wholesale acquisition cost of $515,000 [5], which is in line with the wholesale acquisition costs of approved CAR-T therapies ($424,000-$533,000) [6].
Recent Clinical Data
AMTAGVI’s FDA approval was based on a Phase II trial in heavily pretreated patients with unresectable or metastatic melanoma. When combined with pembrolizumab, AMTAGVI achieved a 31% response rate, and 42% of responses lasted ≥24 months. ~23% of all treated patients had 5-year survival, demonstrating durability in responses (Figure 3). All patients had grade ≥3 adverse events, but all adverse events were expected and consistent with lymphodepletion and IL-2 regimens [7]. Iovance also has a Phase III trial in progress that will compare AMTAGVI plus pembrolizumab against pembrolizumab alone in untreated patients [8].
AMTAGVI aside, other TILs have also already shown promise over standard-of-care treatments. For example, TIL therapy M14TIL beat ipilimumab monotherapy in a Dutch Phase III trial of 168 patients with unresectable Stage IIIC-IV melanoma, winning it coverage from the Dutch National Health Care Institute. (Ipilimumab monotherapy is a standard second-line treatment for unresectable melanoma patients in the Netherlands [9].) M14TIL achieved a better objective response rate (49% vs 21%), better median overall survival (25.8 months vs 18.9 months), and significantly longer median progression-free survival (7.2 months vs 3.1 months) (Figure 4) [10]. Like with AMTAGVI, all M14TIL patients experienced grade ≥3 adverse events that were manageable and expected of lymphodepleting chemotherapy and IL-2 administration [11].
Commercial Implications
Companies seeking to successfully commercialize TILs will need to go beyond improving manufacturing logistics and generating good clinical data. They will also need to consider strategies to promote adoption and optimize patient selection. Adoption strategies are needed to overcome hesitancy from stakeholders around the complexity and price of TILs. Unlike with CAR-T therapy, TIL therapy does not target one specific antigen or receptor; the manufacturing process simply selects for the cells most effective against the tumor. This can make the TILs’ exact mechanism for fighting a patient’s cancer nebulous and sow uncertainty in patients and providers. Companies will need to combine strong clinical data with focused education and outreach to overcome this hesitation. Payers may also balk at the large price tag of TIL therapy and push back in the form of utilization management and restrictions, or consider managing its costs with outcomes-based payments.
Companies will also need to consider which patient segments would be most appropriate for treatment. Patients can’t be too early-stage: TIL therapy hinges on harvesting a patient’s tumor and extracting its infiltrated T cells, so the tumor must be sufficiently large. Patients can’t be too late-stage, either: if they are too weak, their T cells may be less effective as their cancer evolves to evade the immune system. Additionally, patient prognoses must be at least as long as the 4-6 weeks it takes to manufacture the TIL therapy. Optimizing patient selection would pay large dividends: as evidenced by AMTAGVI’s and M14TIL’s trials, responders can have extraordinarily long response durations, leading to progression-free survival and overall survival exceeding 5 years. Improving methods for identifying these responders will help deepen our understanding of TIL therapies and further advancements to unlock their potential.
Notes
[1] TIL Therapy | Moffitt Cancer Center (moffitt.org)
[2] TIL Therapy Explained | American Association for Cancer Research (aacr.org)
[3] Average adoption ramp determined by Health Advances analysis and adoption ramps of Breyanzi, Carvykti, and Yescarta.
[4] Sample collection and processing in TIL therapy development | Cytiva Life Sciences
[5] FDA approves first T-cell therapy for a solid tumor (fiercepharma.com)
[6] Redbook. Range covers 2024 wholesale acquisition costs of Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, and Yescarta.
[7] PowerPoint Presentation (iovance.com)
[10] Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma - PubMed (nih.gov)
[11] Cell Therapy Improves Progression-Free Survival in Advanced (esmo.org)
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Matthew Chin is a senior analyst and member of the Biopharma Practice at Health Advances.
Meghan Lu is a senior analyst and member of the Biopharma Practice at Health Advances
Earl Gillespie, PhD, is a Senior Director and Leader of the Biopharma Practice at Health Advances.
Ned Wydysh, PhD is a Vice President and co-leader of Health Advances’ Oncology and Cell and Gene Therapy Practices
Vivek Mittal, PhD is a Partner, Managing Director, and co-leader of Health Advances’ Oncology and Cell and Gene Therapy Practices