Dendritic Cell Vaccines Presenting Autologous Tumor Antigens from Self-renewing Cancer Cells in Metastatic Renal Cell Carcinoma

Tumor progression

Tumor Progression

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Summary

This study aims to investigate the effects of patient-specific Dendritic Cell vaccines and self-renewing autologous tumor cells in patients with metastatic renal cell carcinoma. The result showed this patient-specific vaccine approach is feasible, well-tolerated, and associated with encouraging long-term survival in some patients.

Patients characteristics

9 patients with histologic diagnosis of renal cell carcinoma (RCC), Karnofsky performance status ≥70, Eastern Cooperative Oncology Group performance level of 0–2, satisfying usual phase II clinical trial criteria for hematologic, metabolic, renal and hepatic chemistry tests. At the time of treatment, patients had to be 16 years of age or greater. Patients with brain metastases were eligible if known tumors had been controlled with therapy and they were not taking pharmacologic doses of corticosteroids.

Treatment

At the time of each treatment, a cryopreserved vial of DCV was thawed and suspended in 500 micrograms of GM-CSF and injected withing 5 hours of thawing. Subcutaneous injections were administered during weeks 1, 2, 3, 8, 12, 16, 20 and 24. Concurrent anticancer therapy was not allowed.

Results

The vaccine was well-tolerated except for mild to moderate pain and erythema at the injection site in 5/9 patients (3 grade-2, 2 grade-1), and 1 patient (#5-RK) experienced an anaphylactoid reaction. The highest grade of toxicity experienced by any individual patient was 3 with grade 0, 1 with grade 1, 4 with grade 2, 1 with grade 3, and 0 with grade 4. One grade 2 AE was bone discomfort that was attributed to GM-CSF since the patient had no bone metastases. Clinical outcomes by patient
Patient #1-RR had spinal compression from metastases with leg weakness at the time of initial diagnosis. He discontinued treatment after three vaccinations because of recurrent problems in the area of prior spine surgery. PFS of 1.4 months and OS 25.5 months.DCs were derived from peripheral blood mononuclear cells (PBMCs) obtained during a single leukapheresis procedure processing 1.5 to 2 L blood volume. Cellular components in the PBMC product were estimated using a Coulter counter. Monocytes were enriched from the apheresis PBMC product using Ficoll density gradient centrifugation. Monocytes were differentiated into DCs over 6 days by culturing in the presence of granulocyte-macrophage colony- stimulating
factor (GM-CSF) and IL-4.
Patient #2-HS had lung and bone lesions at the start of treatment that did not progress during treatment but did progress about 11 months after completing the series of injections. Progressive disease 11 months later. PFS of 16.4 months and OS 27.4 months.
Patient #3-DD had presented with spinal compression from metastases at the time of initial diagnosis. PFS 1.9 months and OS of 13.3 months.
Patient #4-CG had presented with left cervical adenopathy that persisted at the start of DCV. Scans showed progression of cervical and retroperitoneal lymph nodes during DCV therapy, but she completed all eight doses. PFS of 1.7 months and OS 13.3 months.
Patient #5-RK had recurred 4 years after original nephrectomy and adjuvant auto-lymphocyte therapy. At baseline, he had measurable pulmonary lymph node metastases that remained stable throughout treatment. These eventually resolved several months after completing the series of DCV injections. He subsequently progressed in the brain and was treated with gamma knife. After that, he remained disease free and was still alive at 5 years.
Patient #6-DC developed bilateral lung metastases 4 years after the original diagnosis. These responded to IL-2, and a residual lung lesion was resected and was the source of ITCs for the vaccine. He had no measurable disease at the time of treatment. He remained disease free after 5 years.
Patient #7-JO had metastatic disease that included several lung nodules (largest 3.1 cm in the right basilar area), and cytologically-proven malignant pleural effusion. When he started the vaccine in May 2004, a 1.0 cm lung lesion persisted as the only site of measurable disease. This lesion remained stable initially then slowly resolved such that 7 months after starting therapy, in November 2004, his scans were interpreted as showing no metastatic disease and, therefore, in complete remission. He subsequently was diagnosed with a brain metastasis that was treated with gamma knife. He remained disease free and was still alive at 5 years.
Patient # 8-JM had familial RCC. More than 2 years after undergoing nephrectomy, he presented with pulmonary symptoms and was found to have multiple lung metastases and recurrence in the renal bed that were present when DCV was initiated. DCV was discontinued after three doses because of progression. He subsequently was treated with high-dose IL-2. PFS of 1.8 months and OS 5.7 months.
Patient #9-LL had extensive lung metastases when originally diagnosed. He had some response to sorafenib prior to starting DCV. He progressed during DCV treatment but completed all 8 doses. He subsequently again briefly responded to sunitinib; after progression, a trial of inhaled GM-CSF was discontinued because of toxicity. He survived an additional 8 months without therapy. PFS of 1.9 months and OS 26.1 months.

Conclusion

In this study, there was evidence of clinical activity for a patient-specific DCV on the basis of two delayed complete remissions, and an observed 5-year survival rate of 33%. This was achieved with minimal toxicity. Larger trials of DCs with autologous tumor antigens derived from self- renewing tumor cells, rather than bulk tumor, may be warranted, especially as an adjunct toother therapies, but the autologous tumor cell lines must be produced more rapidly and reliably for this to be practical.

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Scientific article publishing date :7/30/2018

Immucura identifier :BSC21_082EN

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