A phase I/IIa clinical trial in stage IV melanoma of an autologous tumor–dendritic cell fusion (dendritoma) vaccine with low dose interleukin 2

OS rate

Overall survival rate

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Summary

In this phase I/IIa trial, the study investigated the safety and efficacy of a dendritoma vaccine, an active, specific immunotherapy, in stage IV melanoma patients. The result showed a minimal toxicity profile with potential clinical benefit.

Patients characteristics

25 patients with stage IV melanoma patients with the median age of 62 years old (52–68 years old). All patients had progressed to stage IV disease before enrollment, but six had no evidence of disease (NED) prior to inoculation. Five of the NED patients underwent oncologic surgical resection, while one patient underwent radiation and chemotherapy and was deemed NED prior to initiation of the dendritoma vaccinations. Expected survival of 3–6 months and Eastern Cooperative Oncology Group (ECOG) performance status of ≤3.

Methodology

Blood (200 ml) was withdrawn from the patient at least 2 weeks prior to initial vaccination. Serum was prepared from it using standard techniques. Prior to use, the serum was heat-inactivated by incubating at 56 ̊C for 30 min. This autologous serum comprised 10% by volume of the media used for maintenance of patient’s tumor cells and DCs.
Mature DCs were generated from the patient’s peripheral blood monocytes (PBMCs). Sodium- heparinized peripheral blood (300 ml) was obtained from the patient. PBMC’s were isolated by Ficoll-Paque Plus gradient. Monocytes were then isolated from the PBMC’s by panning for 3-4 h in petri dishes. The purified monocytes were then cultured in complete DC medium (RPMI-1640 +10% human serum + GM-CSF + IL-4) at 37 ̊C, 5% CO2 for 7-10 days to generate dendritic cells.

Treatment

Phase I, patients were inoculated with doses of 0.25−1.0×106 dendritomas every 3 months, up to a maximum of five vaccinations. Starting day one after the first inoculation of dendritoma, IL-2 was administered daily by subcutaneous injection for a total of 5 days. IL-2 doses started at 3mIU/ m2/day and increased by 3mIU/m2/day to a maximum dose of 9mIU/m2/day. Each patient was pre-medicated 1 h prior to IL-2 injection with Claritin (10 mg) and Celebrex (100 mg) or Relafen (1000 mg). Inoculations two through five were administered in similar fashion to the initial, but without IL-2.
Phase IIa, patients were vaccinated with doses from 0.1−1.0 × 106 dendritomas every 6 weeks up to six vaccinations. IL-2 at a dose of 3mIU/m2/day was given on post-vaccination days one, three and five after the first inoculation. Again, re-vaccination was similar to the first, but without IL-2.

Results

ToxicityAll study drug-related toxicity was less than grade 3 with flu-like symptoms being the most common. The most common adverse events include systemic fever (60 %), chills (32 %), nausea (28 %), arthralgias/myalgias (28 %) and erythema (20 %). Phase I had greater toxicity over- all (p = 0.004), although phase IIa patients had a non- significant increase in neurologic and skin manifestation (p = 0.61 and p = 0.79, respectively). The skin- specific toxicities from both trials appeared after the IL-2 administration and included bruising, erythema, facial flushing and swelling, pruritus, rash and local swelling; there were no skin-specific toxicities following the dendritoma administration.
Clinical outcomes
Median overall survival (OS) was 16.1 months with projected 5-year survival = 29 %. Significant OS improvement for patients receiving ≥3 versus <3 inoculations (43.1 vs. 16.7 %, p = 0.02) was observed. Patients with no evidence of disease (NED) showed improved OS (80 vs. 14 %). No clinicopathologic differences were present between phase I (n = 10) and IIa (n = 15) patients; phase IIa patients received more frequent dosing and higher mean number of inoculations. Phase IIa median OS was significantly higher (23.8 vs. 8.7 months).
Phase IIa patients had a significantly increased median OS compared to phase I patients (28.7, IRQ 15.7–29.8 vs. 8.7, IRQ 2.9–11.7 months). On 5-year projected survival analysis, phase IIa patients again had a significantly increased survival compared to phase I (41.1 vs. 10 %). There were more NED patients in the Phase IIa trial, though the difference was not statistically significant (33 vs. 10 %, p = 0.12). If the NED prior to inoculation patients were excluded from both trials, the 5-year estimated survival was 26.7 vs. 0 % (IIa vs. I, respectively).

Conclusion

In this phase I/IIa trial of the dendritoma vaccine for advanced stage melanoma, this shows potential promising results compared to historical controls. Importantly, also shows this vaccine to have a minimal toxicity profile.

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Scientific article publishing date : 19/02/2016

Immucura identifier :BSC21_067EN

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