Personalized Dendritic Cell Vaccination Safe, but More Research Needed on Efficacy

Autologous tumor lysate particle-loaded dendritic cell (TLPLDC) vaccination is well-tolerated in combination with other immunotherapies, but further research is needed to confirm its efficacy.

Melanoma patients with metastatic disease face low survival rates despite the advent of immunotherapies, which have changed the way many cancers, including melanoma, are treated. Open-label trial results published in Melanoma Research suggest that autologous tumor lysate particle-loaded dendritic cell (TLPLDC) vaccination, in addition to systemic standard-of-care therapies, is well-tolerated and safe, presenting a potential option to overcome the limitations of immune checkpoint inhibitors (ICIs) alone if future trials find the combination to be effective.

The current recommended first-line systemic treatments for metastatic melanoma are BRAF/MEK inhibitors and ICIs, including ipilimumab, nivolumab, and pembrolizumab. These treatments have led to better outcomes, but not all patients respond to them and treatment failures are common. Combining ICIs (such as nivolumab plus ipilimumab in the CheckMate 067 trial) has shown slight improvement, but it is associated with significant toxicity that leads up to 40% of patients to stop treatment.

Combining different types of immunotherapy, such as ICIs in combination with cell-based vaccines, is another potential treatment option. TLPLDC is a personalized cancer vaccine that was designed to prevent recurrence in resected metastatic melanoma, and it has been shown to be safe as an adjuvant therapy for patients with resected stage III or IV melanoma. However, researchers hypothesize that the vaccine might work synergistically with ICIs when the two are combined.

The current exploratory study was an open-label trial that initially included patients with metastatic melanoma treated with a TLPLDC vaccine or standard-of-care immunotherapies who experienced locoregional recurrence or metastasis during a previous randomized phase 2B trial comparing TLPLDC to a placebo in stage III and IV melanoma. Eligible patients crossed over to this study to receive open-label TLPLDC in addition to standard of care therapies to form the crossover cohort (n = 28). There were 17 patients who had received the vaccine in the previous trial and 10 from the placebo group being vaccinated for the first time. One patient died prior to vaccination, one withdrew, and one was lost to follow-up.

Additional patients with metastatic melanoma who were not enrolled in the phase 2B study were also eligible after the crossover study began (n = 26). Two patients died before vaccination, 2 withdrew, 4 did not have measurable disease, and 2 had progressive disease. TLPLDC was administered to 16 patients in this cohort along with concurrent checkpoint inhibitors.

Before initial or repeat vaccination for this study, patients in the crossover cohort had either residual disease or no evidence of disease due to complete resection before vaccination. Patients from the metastatic melanoma cohort had to have measurable disease as evidenced by tissue collection and were required to receive checkpoint inhibitors concurrently with TLPLDC. Both groups gave tissue to be used in vaccine production before resection or pretreatment biopsy.

The main end point of the study was safety, with a secondary goal of generating hypotheses regarding the combination therapy’s efficacy.

At a median follow-up of 13.9 months, overall survival (OS) was 76.5% in the crossover arm and progression-free survival (PFS) was 57.1%. In the metastatic melanoma arm, OS was 85.7% and PFS was 52.2% at a median follow-up of 8.5 months by intention-to-treat analysis.

Ten patients in the crossover cohort—6 who were revaccinated and 4 who were vaccinated for the first time—had surgery for recurrence and no evidence of disease at the time of vaccination. Two patients in the revaccinated group and 2 from the initial vaccination group recurred. OS was 85.7% and PFS was 75% at a median follow-up of 25.8 months.

Overall, 32 patients had residual disease before vaccination across both cohorts. A total of 16 were in the crossover group, 11 of whom were in the previous study’s vaccination group and 5 who were in the placebo group. Another 16 in the metastatic melanoma group had measurable disease. At a median follow-up of 13.9 months, OS was 76.7% and PFS was 46.1% in the 32 patients who had measurable disease at the time of vaccination. The rate of disease control was 41.2% in the revaccinated cohort versus 30.1% in patients vaccinated for the first time.

A total of 31 treatment-related adverse events (AEs) were reported in the crossover cohort, with 21% of patients experiencing any AE and 17% experiencing treatment-related grade 1 or grade 2 AEs. Injection site irritation and skin induration were the most common treatment-related AEs. In the metastatic melanoma cohort, a total of 80 AEs were reported, 12 of which were treatment-related. Only 12 of the 80 reported were grade 3 or higher, and none were treatment-related. The most frequent AE related to treatment was dizziness, and all of the related AEs were grade 1 except a single grade 2 case of nausea.

The authors conclude, “The TLPLDC vaccine is safe in repeated and prolonged use, as well as in combination with other standard systemic therapies to include CPIs, BRAF/ MEKi, TKI and XRT. Improved disease-control rate in the revaccinated cohort suggests that TLPLDC vaccine may be more beneficial for patients with less tumor burden and less aggressive disease.”

Limitations included the study’s heterogenous population and a lack of control groups or comparable cohorts.

“Importantly, this trial was not powered to evaluate clinical outcomes; the primary aim of the study was to assess feasibility and safety,” the authors wrote. Further studies are needed to confirm the TLPLDC vaccine’s synergy with other immunotherapies and its efficacy.

Reference

Adams A, Chick R, Vreeland T, et al. Safety and efficacy of autologous tumor lysate particle-loaded dendritic cell vaccination in combination with systemic therapies in patients with recurrent and metastatic melanoma. Melanoma Res. 2021;31(4):378-388. doi:10.1097/CMR.0000000000000758