The IMPALA trial (IMmunotherapy Pleural 5-ALA PDT) is investigating whether combining photodynamic therapy with checkpoint inhibitor immunotherapy can improve outcomes for patients with inoperable pleural mesothelioma. Currently recruiting in France, the trial combines two treatment modalities that have each shown activity against mesothelioma but have not previously been tested together.
Results from IMPALA are expected in mid-2026. If the combination proves effective, it could offer a new treatment approach for patients who have limited options after chemotherapy.
What the Trial Is Testing
Photodynamic therapy (PDT): Patients receive a light-sensitizing agent (5-aminolevulinic acid, or 5-ALA) that accumulates preferentially in cancer cells. When exposed to specific wavelengths of light delivered into the pleural cavity, the drug generates reactive oxygen species that kill tumor cells.
Nivolumab (Opdivo): Following PDT, patients receive nivolumab, a PD-1 checkpoint inhibitor already approved for mesothelioma treatment. The theory is that PDT-induced cell death will release tumor antigens that enhance the immune response triggered by nivolumab.
Patient population: The trial enrolls patients with pleural mesothelioma who have not responded to conventional treatment and are not candidates for surgery.
The Rationale for Combination
Combining PDT with immunotherapy is based on several observations:
Immunogenic cell death: PDT kills cancer cells in a way that may stimulate immune responses. The dying cells release damage-associated molecular patterns (DAMPs) and tumor antigens that can activate T cells.
Immune checkpoint synergy: Checkpoint inhibitors like nivolumab work by releasing the brakes on immune responses. If PDT provides a stronger antigenic stimulus, the combination may produce more robust anti-tumor immunity.
Prior PDT experience: Earlier trials of PDT alone for mesothelioma showed that some patients achieved extended survival, suggesting the approach has activity against this cancer.
Limited surgical options: Many mesothelioma patients are not candidates for surgery. PDT offers a minimally invasive way to reduce tumor burden in the pleural space.
History of PDT for Mesothelioma
Photodynamic therapy for mesothelioma has been studied since the 1990s, primarily as an adjunct to surgery:
University of Pennsylvania studies: Researchers led by Dr. Keith Cengel and others tested intraoperative PDT following surgical resection. Early trials used various photosensitizers including Photofrin (porfimer sodium) and Foscan (temoporfin).
Phase III trial (1997): A randomized trial comparing surgery alone to surgery with intraoperative PDT found no significant survival difference in the overall population, though subset analyses suggested potential benefit in certain patient groups.
6-year follow-up: Long-term follow-up of PDT-treated patients identified some extended survivors, prompting continued investigation of the approach.
Technical challenges: PDT for mesothelioma requires specialized equipment to deliver light uniformly throughout the pleural cavity. Few centers have developed the necessary expertise and infrastructure.
What We Know About PDT Effectiveness
Results from earlier PDT studies for mesothelioma:
Median survival: Clinical trials have reported median survival ranging from 10 months to approximately 3 years depending on patient selection and treatment protocols.
Response patterns: PDT appears to work best against superficial disease on the pleural surfaces. Bulky tumor or deep tissue invasion may not receive adequate light penetration.
Safety profile: PDT causes photosensitivity, requiring patients to avoid sunlight for several days after treatment. Other side effects include pain, inflammation, and potential damage to adjacent structures if light is not properly directed.
Limited adoption: Despite decades of research, PDT has not become standard treatment for mesothelioma due to mixed efficacy results, technical complexity, and limited availability.
IMPALA represents a shift in how PDT is being tested—using it to trigger immune responses rather than as a standalone tumor-killing treatment. The combination with nivolumab aims to sustain anti-tumor immunity initiated by PDT-induced immunogenic cell death.
How the IMPALA Trial Differs
The IMPALA trial represents a new approach to PDT for mesothelioma:
Non-surgical setting: Rather than using PDT during surgery, IMPALA delivers therapy to patients with inoperable disease, potentially expanding who might benefit.
Combination strategy: Adding nivolumab addresses the limitation that PDT alone may not produce durable responses. The immune checkpoint inhibitor may sustain anti-tumor immunity initiated by PDT.
5-ALA photosensitizer: The trial uses 5-aminolevulinic acid rather than older photosensitizers. 5-ALA has a shorter duration of photosensitivity and may have improved tumor selectivity.
Modern trial design: IMPALA incorporates current understanding of immune responses to PDT and aims to optimize timing between PDT and immunotherapy initiation.
Current Trial Status
As of early 2026:
Location: The trial is currently recruiting at sites in France.
Enrollment: The trial is actively enrolling patients who meet eligibility criteria.
Timeline: Results are expected to be available by mid-2026.
Eligibility: Patients must have pleural mesothelioma that has progressed after prior treatment and must not be candidates for surgical resection.
What This Could Mean for Patients
If results are positive: A successful IMPALA trial could lead to expanded studies and potentially establish PDT plus immunotherapy as a treatment option for patients with limited alternatives.
If results are negative: Even a negative result would provide valuable information about the biology of mesothelioma and immune responses to PDT, guiding future research directions.
Current availability: PDT for mesothelioma is available only through clinical trials at specialized centers. Patients interested in this approach should discuss trial options with their oncologists.
Related Clinical Trials
Several other trials are exploring novel approaches for mesothelioma:
- CAR-T cell therapy trials targeting mesothelin
- Tumor treating fields (TTFields) in combination with chemotherapy
- Novel checkpoint inhibitor combinations
- Targeted therapies for specific genetic alterations
Patients with mesothelioma should discuss clinical trial options with their treatment team, particularly if they have progressed on standard therapies.
What is photodynamic therapy?▼
PDT uses a light-sensitizing drug (in IMPALA, 5-aminolevulinic acid) that accumulates in cancer cells. When exposed to specific wavelengths of light delivered into the pleural cavity, the drug generates reactive oxygen species that kill tumor cells. PDT kills cells in a way that may trigger immune responses.
Why combine PDT with immunotherapy?▼
PDT causes immunogenic cell death—dying cancer cells release damage-associated molecular patterns and tumor antigens that can activate T cells. Adding nivolumab, which releases the brakes on immune responses, may enhance and sustain this anti-tumor immunity for more durable responses.
Who is eligible for IMPALA?▼
The trial enrolls patients with pleural mesothelioma that has progressed after prior treatment and who are not candidates for surgical resection. The trial is currently recruiting at sites in France, with results expected mid-2026.
What has earlier PDT research shown?▼
Prior studies of PDT for mesothelioma reported median survival ranging from 10 months to about 3 years depending on patient selection. PDT works best against superficial disease on pleural surfaces. A 1997 Phase III trial showed no significant overall survival difference vs. surgery alone, though some long-term survivors were identified.