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

Our plain-English summary of Phase II Trial of Adjuvant Dendritic Cell Vaccine in Combination with Celecoxib, Interferon-α, and Rintatolimod in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases, by R. Ramanathan, H. Choudry, H. Jones, et al (Annals of Surgical Oncology, 2021).

The study

• Authors: R. Ramanathan, H. Choudry, H. Jones, M. Girgis, W. Gooding, P. Kalinski, D.L. Bartlett
• Journal: Annals of Surgical Oncology
• Published: 2021;28(8):4637-4646
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Peritoneal metastases portend poor prognosis in the setting of standard chemotherapy. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) improves outcomes, but relapse is common. We report a phase II trial evaluating the safety and efficacy of adjuvant αDC1 vaccination with chemokine modulation (CKM) after CRS/HIPEC.

Methods: Patients undergoing CRS/HIPEC for appendiceal cancer, colorectal cancer, or peritoneal mesothelioma were enrolled. In addition to standard adjuvant chemotherapy, patients received intranodal and intradermal injections of autologous tumor-loaded αDC1 vaccine. After each vaccine booster, patients received CKM over 4 days, consisting of celecoxib, interferon (IFN)-α, and rintatolimod.

Results: Forty-six patients underwent CRS/HIPEC followed by αDC1 treatment, including 24 appendiceal primaries, 20 colorectal, and 2 mesotheliomas. DC maturation was successful, with 97% expressing HLA-DR and CD86. Tumor cell recovery from peritoneal tumors was challenging, resulting in only 17% of patients receiving the target dose of αDC1. The αDC1 and CKM regimen was well tolerated. CKM successfully modulated serum inflammatory cytokine and chemokine levels. Median progression-free survival (PFS) for appendiceal primaries was 50.4, 34.2, and 8.9 months for grade 1, 2, and 3 tumors, respectively, while median PFS for colorectal cancer was 20.5 and 8.9 months for moderately and poorly differentiated tumors, respectively.

Conclusions: Adjuvant autologous tumor antigen-loaded αDC1 vaccine and CKM is well tolerated. The mucinous nature of peritoneal metastases limits the feasibility of obtaining adequate autologous tumor cells. The improvement in median PFS did not meet our predefined thresholds, leading us to conclude that αDC1 vaccination is not appropriate for patients undergoing CRS/HIPEC for peritoneal metastases.

In plain English

This single-institution phase II trial tested a vaccine given after cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC). The vaccine was made from each patient's own dendritic (immune) cells loaded with their own tumor cells. After each vaccine booster, patients also received a four-day drug course: interferon-alpha and celecoxib on days 2 to 5, and rintatolimod on days 3 and 5. Of 63 patients enrolled, 46 were reported: 24 with appendiceal cancer, 20 with colorectal cancer and 2 with peritoneal mesothelioma. The article does not discuss asbestos exposure. Too few tumor cells could be recovered, so only 9 of 46 patients received the target vaccine dose and 8 of 46 received all three boosters at that dose. Mild flu-like symptoms were the most common side effects. Six patients had grade 3 to 5 events possibly due to treatment. Blood inflammatory markers rose after treatment. The two mesothelioma patients had recurrences at 25 and 8 months and died at 40 and 10 months. The trial was stopped early for futility. The authors concluded the vaccine is not appropriate for patients undergoing CRS/HIPEC for peritoneal metastases.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-institution phase II clinical trial (University of Pittsburgh, NCT02151448), stopped early after an interim analysis
• Who was studied: 63 patients undergoing CRS/HIPEC for peritoneal metastases were enrolled. 46 were analyzed: 24 with appendiceal cancer, 20 with colorectal cancer and 2 with peritoneal mesothelioma. There were 15 women and 31 men, with a mean age of 55. Enrollment dates are not given in the article.
• Exposure: This was a treatment study, not an asbestos-exposure study. Patients received an autologous tumor-loaded alpha-type-1 dendritic cell vaccine, injected into the skin and lymph nodes. After each booster came chemokine modulation: intravenous interferon-alpha on days 2 to 5, intravenous rintatolimod (200 mg) on days 3 and 5, and oral celecoxib (200 mg) twice daily on days 2 to 5. Standard chemotherapy was allowed at the same time.
• Main results:
  • Because too few tumor cells were recovered, only 9 of the 46 patients received the target vaccine dose.
  • Only 8 of the 46 patients received all three boosters at the target dose.
  • No patient reached the intended 30:1 ratio of dendritic cell precursors to tumor cells.
  • Grade 1 flu-like symptoms were the most common side effects attributed to treatment. Six of the 46 patients had grade 3 to 5 adverse events possibly attributed to treatment.
  • All measured blood inflammatory cytokines and chemokines increased after the first booster with chemokine modulation (p less than 0.01 for each in Table 4).
  • Colorectal cancer patients had a median progression-free survival of 20.5 months for moderately differentiated tumors and 8.9 months for poorly differentiated tumors.
  • Appendiceal cancer patients had a progression-free survival of 50.4 months for grade 1, 34.2 months for grade 2 and 8.9 months for grade 3 tumors.
  • Both peritoneal mesothelioma patients had biphasic mesothelioma. Their disease recurred at 25 and 8 months, and they died of their disease at 40 and 10 months.
  • The trial was terminated early after an interim analysis showed futility. The reasons given were lack of improvement in progression-free survival (colon cancer), variable tumor grade affecting results (appendiceal cancer) and slow accrual (mesothelioma). Target accrual had been 168 patients.
• The authors' conclusion: The authors concluded that the vaccine with chemokine modulation was well tolerated. Because the improvement in progression-free survival did not meet their predefined thresholds, they judged the vaccine not appropriate for patients undergoing CRS/HIPEC for peritoneal metastases. They also concluded that the mucinous nature of these tumors limits how many of the patient's own tumor cells can be obtained.
• Limitations the authors state:
  • The authors said the below-target tumor-cell loading ratio likely impaired vaccine maturation and limited its clinical impact.
  • Because the treatment was given after surgery, the authors could not document changes inside tumors. They measured only blood levels of these markers.
  • The authors could not confirm earlier laboratory observations about the immune profile of the tumor environment.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Colon cancer.

Medical terms in this study, explained in our Lexicon: Cytoreductive Surgery, HIPEC, Prognosis, Chemotherapy, Colorectal Cancer, Peritoneal Mesothelioma, Mesothelioma, Cytokine.

Related studies

• Adjuvant dendritic cell-based immunotherapy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with malignant peritoneal mesothelioma: a phase II clinical trial — M.V. Dietz, K.L.A. Quintelier, et al. (2023)
• Adjuvant dendritic cell based immunotherapy (DCBI) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma, a phase II single centre open-label clinical trial: rationale and design of the MESOPEC trial — N.L. de Boer, J.P. van Kooten, et al. (2019)
• Assessing morbidity, mortality, and survival in patients with peritoneal carcinomatosis undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy — J.S.A. Vallejo, F.L. Queiroz, et al. (2023)
• Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion in Adolescent and Young Adults with Peritoneal Metastases — M. Dhir, L. Ramalingam, et al. (2017)
• The results of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in 1200 patients with peritoneal malignancy — B. Moran, T. Cecil, et al. (2015)
• A Canadian single-centre experience with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for abdominal malignancies — R. Nassabein, R. Younan, et al. (2022)

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