Phase II Trial of Adjuvant Dendritic Cell Vaccine in Combination with Celecoxib, Interferon-a and Rintatolimod in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases

Overall Survival

Overall Survival

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Summary

This study aims to demonstrate the safety and efficacy of adjuvant αDC1 vaccination with chemokine modulation (CKM) after Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) on patients diagnosed with peritoneal metastases. The results conclude that αDC1 vaccination is not appropriate for patients undergoing CRS/HIPEC for peritoneal metastases.

Patients characteristics

46 patients included 15 females and 31 males with a mean age of 55 years. Twenty-four patients had appendiceal peritoneal metastases, 20 patients had colorectal peritoneal metastases, and 2 patients had peritoneal mesothelioma. Overall, 34 (74%) patients had recurrent disease at presentation, 32 (70%) had undergone previous CRS, and 20 (43%) had previously undergone HIPEC. On average, patients had been diagnosed with peritoneal metastases for 27 months prior to treatment. Eastern Cooperative Oncology Group (ECOG) performance status of 0–2.

Methodology

Patients underwent leukapheresis preoperatively or within 8 weeks after CRS/ HIPEC for extraction of DC. Monocytes were isolated by Elutra Cell Separation System. These were cultured in antibiotic- free culture medium supplemented with 1000 U/mL IL-4 and 1000 U/mL granulocyte–macrophage colony stimulating factor (GM-CSF) for 6 days to generate immature DC. Immature DC were cryopreserved until vaccination.
Prior to vaccination, immature DC were recovered from cryopreservation and polarized with IL- 1b (25 ng/mL), TNF- (50 ng/mL), IFN- (3000 U/mL), poly-I:C (20 mg/mL), and IFN (1000 U/mL) at 37 °C in 5% CO2 for 48 hours. Tumor specimens were collected at the time of the surgery. Fresh tissue was minced and digested with collagenase and DNase. Lysates were sterilized with ultraviolet B (UVB) and treated with c- irradiation (20,000 Rads) to induce apoptosis.
Apoptotic tumor cells were added to the immature DC cultures at day 6, during the induction of DC maturation into polarized DC1 at a target ratio of 30:1 monocyte to tumor cells. This corresponds to an estimated ratio of 10:1 DC1 to tumor cells, since typically 10 monocytes yield 2–3 DCs. Mature antigen-loaded DC1 were harvested after 48 hours.

Treatment

Vaccines were delivered intradermally and intranodal using ultrasound guidance, rotating between the left and right inguinal lymph node clusters. After the patient recovered from CRS/HIPEC, a priming dose of aDC1 was administered on the first week of treatment. The priming dose consisted of both intradermal and intranodal injections of DC1 vaccine alone.Within 4 weeks, patients received a booster cycle consisting of both intradermal and intranodal injections of DC1 vaccine followed by 4 subsequent days of CKM. The chemokine modulation (CKM) consisted of intravenous IFN (20 mu/m2) on days 2–5, intravenous rintatolimod (200 mg) on days 3 and 5, and twice-daily oral celecoxib (200 mg) on days 2–5.
In those without adverse events (AE), two additional booster cycles were offered every 4 weeks using the same aDC1/CKM regimen. Patients could receive standard-of-care adjuvant chemotherapy concurrently. Adjuvant chemotherapy was administered between vaccine therapies but no sooner than 5 days after completing a cycle of vaccine therapy.

Results

Adverse events
Grade 1 flu-like symptoms were the most common AEs attributed to the DC vaccination and CKM, including chills (n = 36), fatigue (n = 19), and nausea (n = 19). They were usually self-limited to 24 hours after each vaccine dose. Grades 1 and 2 injection-site reactions were relatively uncommon, affecting only two patients. Six patients had grades 3–5 AEs, possibly attributed to treatment.
These included a decrease in lymphocyte count, diarrhea, transient blurry vision, stroke, heart failure, and gastrointestinal bleed while receiving blood thinners for personal history of stroke. One patient experienced transient blurry vision that may be related to rintatolimod and was self- limited.
Clinical Outcomes
Progression-free survival (PFS) for colon cancer was 20.5 months for moderately differentiated tumors, and 8.9 months for poorly differentiated tumors. Two of 11 patients with moderately differentiated tumors have not recurred at 58 and 46 months after CRS/HIPEC. Both had PCI scores of <12 and had all gross disease removed at the time of surgery. Overall survival for the moderately differentiated tumors was not reached, and for poorly differentiated tumors was 18.3 months.
For appendiceal cancers, PFS was 50.4 months for low- grade (grade G1), 34.2 months for intermediate-grade (grade G2), and 8.9 months for high-grade/poorly differentiated/signet ring cell cancers (grade G3). Three of eight patients with grade G2 tumors have not recurred at 55, 44, and 35 months of follow-up, with PCI scores of 8, 3, and 28, respectively, and all gross disease removed. Four of seven patients with grade G1 tumors have not recurred at 55, 51, 49, and 45 months, with PCI scores of 10, 14, 16, and 10, respectively, and all gross disease removed. Three of eight patients with grade G3 tumors have died of their disease at 6, 7, and 8 months after surgery; the remaining five patients are still alive 30–46 months after surgery. One of eight patients with grade G2 tumors had died at 44 months, with the remaining seven patients were alive 35–56 months after surgery. All patients with grade G1 tumors were still alive at a median follow-up of 50 months. The two patients with mesothelioma recurred at 25 and 8 months and died of their disease at 40 and 10 months, respectively.

Conclusion

This study demonstrates the safety of CKM in combination with autologous tumor pulsed DC1 vaccine and shows that chemokine modulation (CKM) elicits a heightened inflammatory state in the serum. It also illustrates the logistical challenges with isolating sufficient cancer cells to generate sufficient numbers of autologous tumor-pulsed DC1 immune therapy in patients with peritoneal metastases.

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Scientific article publishing date 15/1/2021

Immucura identifier BSC21_061EN

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