Immunotherapy + Vaccine for Liver Cancer

Overseen By Clinical Trials Referral Office

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Mayo Clinic

Must not be taking: Antiretrovirals, Corticosteroids

Disqualifiers: Pregnancy, Immunocompromised, Autoimmune diseases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 21-28 days per cycle, up to 7 cycles

85 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination to help the immune system fight liver cancer that cannot be surgically removed. The treatment uses a pneumonia vaccine (Pneumococcal 13-valent Conjugate Vaccine), special immune cells from the patient's own body (Therapeutic Autologous Dendritic Cells), and medication that helps the immune system target cancer cells. Researchers aim to determine if this combination is safe and effective after patients have undergone high-dose radiation treatment. It suits those with liver cancer that is not removable by surgery and who have already received radiation therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on corticosteroids, you may need to adjust your dosage to less than 10 mg/day of prednisone (or equivalent) to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that each component of this trial treatment has promising safety results from previous studies.

First, external beam radiation therapy (EBRT) for liver cancers has proven effective in controlling the disease in the liver. Some patients may experience changes in liver function or issues with bile ducts, but these are known side effects that are monitored.

Autologous dendritic cells, derived from a patient's own blood, have been used to enhance the immune system's response to tumors. Studies suggest this method is safe, with previous patients showing improved survival rates and minimal side effects.

The Prevnar vaccine, which boosts the immune system against infections, is well-tolerated. It has a strong safety record in adults, with only mild side effects like soreness at the injection site.

Atezolizumab, a type of immunotherapy, has been used successfully in liver cancer patients and has a good safety profile, with manageable common side effects. When combined with bevacizumab, which reduces blood supply to tumors, the combination is considered safe and effective, though it can affect liver function in some cases.

Tiragolumab, when combined with atezolizumab, does not introduce new safety concerns. It might cause mild skin rash or itching in some individuals.

Overall, each part of this trial treatment has been tested in humans, demonstrating it is generally safe and well-tolerated. However, monitoring for side effects remains important. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for liver cancer because they combine immunotherapy with innovative delivery methods. Unlike traditional therapies, which often rely on chemotherapy or surgery, these treatments use a combination of external beam radiation therapy (EBRT) and autologous dendritic cells, which are personalized immune cells designed to target cancer. Additionally, the use of vaccines like the pneumococcal 13-valent conjugate vaccine aims to boost the immune response against cancer cells. In some study arms, the inclusion of drugs like atezolizumab, bevacizumab, and tiragolumab adds further layers of immune modulation, potentially offering a more comprehensive attack on the cancer. This multifaceted approach could provide more effective and personalized treatment options for patients with unresectable liver cancers.

What evidence suggests that this trial's treatments could be effective for liver cancer?

Research has shown that external beam radiation therapy (EBRT) can effectively treat liver cancers that cannot be surgically removed. It helps control tumor growth in some patients. In this trial, participants in different arms will receive various combinations of treatments. Some will receive autologous dendritic cells, which studies have found can help the body fight cancer. The Prevnar vaccine might further boost the immune system to help control the cancer.

In other arms, participants will receive immunotherapy drugs like atezolizumab and tiragolumab, which help the immune system find and destroy cancer cells. Bevacizumab, included in some treatment arms, works by cutting off the blood supply that tumors need to grow. Together, these treatments might help slow down or stop liver cancer from spreading. ^{6 7 8 9 10}

Who Is on the Research Team?

Lewis R. Roberts, MD, PhD

Principal Investigator

Mayo Clinic in Rochester

Are You a Good Fit for This Trial?

This trial is for adults with liver cancer that can't be removed by surgery. They must have a certain level of white blood cells, kidney function, and liver function, and not be pregnant or nursing. People with other active cancers, recent major surgeries, severe allergies to vaccines, HIV on antiretroviral therapy, serious illnesses that could affect the study results or who are taking certain medications are excluded.

Inclusion Criteria

My urine protein levels are low enough for the trial.

My liver cancer has been confirmed by tests and scans.

Prothrombin time/international normalized ratio (PT/ INR) =< 1.5 x ULN (obtained =< 14 days prior to registration)

Exclusion Criteria

My liver cancer is in the most advanced stage.

- Nursing persons

My liver disease is moderately to severely advanced.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Patients undergo high-dose conformal external beam radiotherapy (EBRT) for 5 or 15 fractions over 1-3 weeks

1-3 weeks

Treatment

Patients receive autologous dendritic cells intratumorally and pneumococcal 13-valent conjugate vaccine intramuscularly. In Phase II, patients also receive atezolizumab and bevacizumab intravenously.

21-28 days per cycle, up to 7 cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-ups at 2 weeks, then every 3 months for 1 year, and every 6 months until 5 years after registration.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• External Beam Radiation Therapy
• Pneumococcal 13-valent Conjugate Vaccine
• Therapeutic Autologous Dendritic Cells

Trial Overview The trial tests if modified immune cells (autologous dendritic cells) from patients' own blood can stimulate the immune system to fight liver cancer when given after high-dose radiation therapy. It also examines whether adding Prevnar vaccine enhances this effect. The safety and effectiveness of combining these treatments with immune checkpoint inhibitors will be studied in two phases for different types of liver cancer.

How Is the Trial Designed?

Group I: Pilot study (pheresis, EBRT, dendritic cells, Prevnar) Experimental Treatment 4 Interventions

Patients with unresectable intrahepatic CCA undergo apheresis for dendric cell manufacturing and standard of care high-dose EBRT for 5 or 15 fractions over 1-3 weeks (cycle 1). Patients then receive autologous dendritic cells IT on day 1 of cycles 2-8 and pneumococcal 13-valent conjugate vaccine IM on day 1 of cycles 2-4 only. Treatment repeats every 28 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. (CLOSED WITH AMENDMENT 3)

Group II: Phase II Group 3 (EBRT, dendritic cells, Prevnar, atezo, tir) Experimental Treatment 11 Interventions

Patients with iCCA undergo apheresis for dendric cell manufacturing and standard of care high-dose EBRT for 5 or 15 fractions over 1-3 weeks (cycle 1). Patients then receive autologous dendritic cells IT on day 1 of cycles 2-8 and pneumococcal 13-valent conjugate vaccine or other pneumococcal vaccine IM on day 1 of cycles 2-4 only. Patients also receive standard of care atezolizumab IV over 30-60 minutes and tiragolumab IV over 30-60 minutes starting on day 2 of cycles 2-8. Treatment repeats every 21 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo CT, PET/CT and/or MRI, biopsy and urine and blood sample collection throughout the study.

Group III: Phase II Group 2 (EBRT, dendritic cells, Prevnar, atezo, bev) Experimental Treatment 12 Interventions

Patients with unresectable HCC undergo apheresis for dendric cell manufacturing and standard of care high-dose EBRT for 5 or 15 fractions over 1-3 weeks (cycle 1). Patients then receive autologous dendritic cells IT on day 1 of cycles 2-8 and pneumococcal 13-valent conjugate vaccine or other pneumococcal vaccine IM on day 1 of cycles 2-4 only. Patients also receive standard of care atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes starting on day 2 of cycles 2-8. Treatment repeats every 21 days for up to 7 cycles in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo an EGD at screening and CT, PET/CT and/or MRI, biopsy and urine and blood sample collection throughout the study.

External Beam Radiation Therapy is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in United States as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in Canada as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in Japan as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in China as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Approved in Switzerland as External Beam Radiation Therapy for:

• Various types of cancer, including but not limited to breast, lung, prostate, and brain cancers

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

External beam radiotherapy (EBRT) has been shown to improve survival rates in patients with intermediate to advanced hepatocellular carcinoma (HCC), particularly those with portal vein or inferior vena cava tumor thrombi, extending survival to an average of 10.7 months.

When compared to sorafenib, a commonly recommended treatment for HCC, EBRT demonstrated superior effectiveness in improving patient survival for tumors of similar metastatic size, suggesting it should be considered in treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is it time to adopt external beam radiotherapy in the NCCN guidelines as a therapeutic strategy for intermediate/advanced hepatocellular carcinoma?. Jiang, W., Zeng, ZC.[2018]

Combining local radiotherapy with intratumoral injections of dendritic cells (DC) shows promise in enhancing the immune response against tumors, as suggested by preclinical studies in mouse models.

A pilot study involving 5 patients with high-risk prostate cancer demonstrated that this combination therapy, alongside radiation treatment, could potentially improve immune activity against cancer, indicating a new avenue for cancer treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical opportunities in combining immunotherapy with radiation therapy. Finkelstein, SE., Fishman, M.[2021]

The autologous dendritic cell vaccine (DC-ATA) has shown promising results in over 200 patients with various cancers, demonstrating a well-tolerated treatment with a rapid immune response primarily involving TH1/TH17 cells.

Clinical trials indicate that DC-ATA may lead to durable tumor regressions and improved survival rates, particularly in metastatic melanoma and glioblastoma, suggesting its potential as an effective immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autologous dendritic cells loaded with antigens from self-renewing autologous tumor cells as patient-specific therapeutic cancer vaccines. Dillman, RO., Nistor, GI., Keirstead, HS.[2023]

The phase 1 study involving 14 advanced hepatoma patients demonstrated that direct injection of autologous immature dendritic cells (DCs) combined with radiotherapy is safe, with only mild side effects reported, such as transient fever and fatigue.

The treatment induced a tumor-specific immune response, evidenced by a significant decrease in alpha-fetoprotein (AFP) levels in some patients and increased natural killer (NK) cell activity, suggesting potential efficacy in combating the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of conformal radiotherapy and intratumoral injection of adoptive dendritic cell immunotherapy in refractory hepatoma. Chi, KH., Liu, SJ., Li, CP., et al.[2022]

The combination of intratumoral dendritic cell (DC) administration and fractionated external beam radiation therapy (EBRT) was safe and well tolerated in 17 patients with large high-grade soft-tissue sarcoma, leading to the development of tumor-specific immune responses in 52.9% of patients.

After one year, 70.6% of patients remained progression-free, indicating that this treatment approach not only induced immune responses but also had potential long-term benefits in controlling tumor growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients. Finkelstein, SE., Iclozan, C., Bui, MM., et al.[2021]

External beam radiotherapy (EBRT) after incomplete transarterial chemoembolization (TACE) in 40 patients with hepatocellular carcinoma showed promising oncologic outcomes, with 1-year overall survival at 82.2% and local control rates at 89.1%.

Despite the favorable outcomes, intrahepatic recurrence was the main cause of disease progression, highlighting the need for improved strategies to manage this issue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical efficacy of external beam radiotherapy complementing incomplete transarterial chemoembolization for hepatocellular carcinoma. Park, S., Yoon, WS., Jang, MH., et al.[2021]

The study evaluated the safety and efficacy of a dendritic cell (DC) vaccine in 20 Egyptian patients with advanced hepatocellular carcinoma (HCC), showing that the DC vaccine had minimal adverse effects and no autoimmunity, indicating it is safe for use.

Patients receiving the DC vaccine demonstrated a partial response and stable disease rates, while those on supportive treatment experienced 100% progressive disease, suggesting potential benefits of the DC vaccine, although further research with a larger cohort is needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autologous dendritic cells pulsed with lysate from an allogeneic hepatic cancer cell line as a treatment for patients with advanced hepatocellular carcinoma: A pilot study. Abdel Ghafar, MT., Morad, MA., El-Zamarany, EA., et al.[2020]

External beam radiation therapy (EBRT) is an effective palliative treatment for patients with hepatocellular carcinoma (HCC) and bone metastases, showing a median overall survival of 6 months and a one-year overall survival rate of 23.1% based on a review of 19 studies involving 1613 patients.

EBRT significantly reduces pain in these patients, with an 81.5% response rate and a 26.5% rate of complete pain remission, although careful monitoring for hematologic complications is necessary, as they occurred in 11.5% to 34% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiotherapy for bone metastases of hepatocellular carcinoma: a hybrid systematic review with meta-analyses. Rim, CH., Park, S., Yoon, WS., et al.[2023]

External beam radiation therapy (EBRT) is used as a bridging therapy for liver transplant in patients with hepatocellular carcinoma (HCC), but it is only utilized in 3.5% of patients, indicating a significant gap in treatment options compared to other liver-directed therapies.

The use of EBRT has been increasing at an average rate of 12.2% per year, and it is associated with a 30% increased risk of receiving a liver transplant, although it does not significantly affect the risk of waitlist removal due to clinical deterioration or death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Utilization of External Beam Radiation Therapy for Patients With Unresectable Hepatocellular Carcinoma: An Analysis of the United Network for Organ Sharing Database. Herman, T., Kaempf, A., Schlansky, B., et al.[2022]

Citations

1. practicalradonc.org practicalradonc.org/article/S1879-8500(21)00233-2/fulltext

External Beam Radiation Therapy for Primary Liver Cancers External beam radiation therapy for primary liver cancers: An ASTRO clinical practice guideline. Smith Apisarnthanarax, MD.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9628149/

Efficacy and Safety of External-beam Radiation Therapy for ... Conclusion: Definitive EBRT for unresectable cholangiocarcinoma was feasible and achieved long-term local control in a subset of patients. As ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10035720/

External Beam Radiotherapy for Hepatocellular Carcinoma External beam radiotherapy (RT) has been increasingly used to manage HCC when recommended treatments cannot be applied in real-world clinical practice.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1879850021002332

External Beam Radiation Therapy for Primary Liver Cancers This guideline provides evidence-based recommendations for the indications and technique-dose of external beam radiation therapy (EBRT) in hepatocellular ...

5. dmr.amegroups.org dmr.amegroups.org/article/view/7092/html

External beam radiation treatment of intrahepatic ... This narrative review aims to summarize the currently available evidence for the role of radiation in the treatment of intrahepatic cholangiocarcinoma (ICC).

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12006625/

The safety and efficacy of atezolizumab for recurrent primary ... A recent meta-analysis reported a mean recurrence rate of 16% for HCC, with a median overall survival (OS) of 12.97 months (range, 0.1–112.5 ...

7. ascopubs.org ascopubs.org/doi/10.1200/GO-25-00128

Effectiveness and Safety of Immunotherapy for ... Median overall survival reached 20.6 months in patients with preserved liver function and good performance status. Liver function (albumin- ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12210818/

Safety and efficacy of atezolizumab/bevacizumab in ... We conclude that the combination of atezolizumab and bevacizumab is a safe and effective option for patients with unresectable hepatocellular carcinoma patients ...

9. journal-of-hepatology.eu journal-of-hepatology.eu/article/S0168-8278(21)02241-8/fulltext

Updated efficacy and safety data from IMbrave150 At this updated analysis done 12 months later, median overall survival was 5.8 months longer with atezolizumab plus bevacizumab than sorafenib, ...

10. sciencedirect.com sciencedirect.com/science/article/pii/S2589555924002507

Neoadjuvant atezolizumab plus bevacizumab prior liver ... Among 17 patients who underwent successful liver transplantation following neoadjuvant atezolizumab/bevacizumab, 82% achieved downstaging to within Milan ...