T cell immunotherapy shows promise for treating liver cancer

Personalised immunotherapy reduces the risk of liver cancer recurrence and may lead to tumour regression, according to a pair of studies presented at the 2018 International Liver Congress last month in Paris.

In one study, people who received adjuvant immunotherapy using their own T cells after surgery or local therapies were less likely to experience hepatocellular carcinoma (HCC) recurrence and had significantly longer survival over five years of follow-up.

In the other study, T cells were engineered to recognise hepatitis B virus (HBV) DNA fragments in HCC tumours, an approach that led to shrinkage of liver cancer that had spread to the lungs in one treated patient.

Over years or decades, chronic hepatitis B or C infection, heavy alcohol use and other causes of liver damage can lead to cirrhosis and HCC, a type of primary liver cancer. HCC is often diagnosed late, when it is difficult to treat, and it is a leading cause of cancer-related death worldwide. Antiviral therapy for hepatitis B reduces but does not eliminate the risk of developing liver cancer, and people with hepatitis C who have progressed to cirrhosis remain at risk for HCC even after being cured of the virus.

Immunotherapy is an increasingly important aspect of cancer treatment. Unlike traditional chemotherapy, which kills rapidly dividing normal cells throughout the body in addition to cancer cells, immunotherapy helps the immune system recognise and attack cancer.

Adoptive T cell therapy involves administering immune cells to fight cancer. In an autologous transfer, a sample of T cells is removed from a patient's blood, modified in a laboratory and returned to the same individual. (An allogeneic transfer, such as a stem cell transplant, uses cells from a donor.)

Starting in 2008, Jeong-Hoon Lee of Seoul National University College of Medicine in South Korea and colleagues conducted a Phase 3 trial of the safety and efficacy of adjuvant immunotherapy in people with HCC who had undergone surgical resection, radiofrequency ablation or percutaneous ethanol injection.

The study included 230 participants enrolled at university hospitals in Korea. More than 80% were men and the mean age was approximately 56 years. Over 80% had hepatitis B and about 10% had hepatitis C; two thirds had liver cirrhosis. About 85% had stage 1 HCC and the rest had stage 2. Most had fewer than three tumours, with a median size of about 2 cm.

Participants in this open-label study were randomly assigned to receive immunotherapy or no adjuvant treatment. The immunotherapy consisted of activated cytokine-induced killer cells created by incubating collected T cells with interleukin 2 and an antibody against CD3. Previous studies showed that cytokine-induced killer cells, which have the functional capacity of both T cells and natural killer cells, are active against various tumour types with little effect on normal cells. The activated cells were given intravenously 16 times over 60 weeks.

As reported in 2015, people who received adjuvant immunotherapy had significantly longer recurrence-free survival than those in the control group (44 vs 30 months, respectively), as well as a lower risk of all-cause and cancer-related mortality. People in the immunotherapy group were more likely to experience adverse events (62% vs 41%, respectively), but serious adverse events were uncommon in both study arms.

At this year's meeting, Lee reported findings from an extended follow-up study to assess whether the efficacy of cytokine-induced killer cell immunotherapy would be sustained after completion of treatment.

A total of 162 participants (89 in the immunotherapy group and 73 in the control group) underwent extended follow-up, which ended 60 months after the last participant was randomised, for a median follow-up duration of about 69 months.

During follow-up, people who received the immunotherapy had a significant 33% lower risk of HCC recurrence or death. The 5-year recurrence-free survival rate was 45% in the immunotherapy group versus 33% in the control group. Overall mortality was reduced by 67%. The benefit was most apparent for people with tumours measuring 2cm or more.

"In patients who underwent curative treatment for HCC, significant gain in recurrence-free and overall survival by adjuvant cytokine-induced killer cell immunotherapy was maintained for over 5 years," the researchers concluded.

Lee suggested that the treatment might promote the development of long-lasting memory T cells and natural killer cells that can carry on anti-tumour activity for years after the last immune cell infusion.

Anthony Tan of Duke-NUS Medical School in Singapore presented findings from a study of personalised T cell therapy for HBV-related liver cancer.

HBV can integrate its genetic material into the human genome, and fragments of HBV DNA may be found in HCC tumours in people with hepatitis B, Tan explained as background. In this study, immune cells were engineered to express HBV-specific T cell receptors to enable them to recognise and attack HCC.

After showing in lab studies that T cells could recognise short HBV DNA fragments in tumours that are hepatitis B surface antigen (HBsAg) negative, the researchers analysed the integrated HBV DNA profile of a liver tumour from a 56-year-old man who underwent liver transplantation but developed metastatic HCC recurrence in both lungs. They detected a short sequence of the HBV envelope gene and used a technique known as mRNA electroporation to insert a receptor specific for this sequence into T cells collected from the man.

The man received multiple infusions of the engineered T cells over a 6-month period. Scans done before and after treatment showed a reduction in the size of most HCC tumours in the lungs, and no new tumours appeared in the lungs or the transplanted liver graft. Levels of alfa-fetoprotein, a liver cancer biomarker, decreased with each infusion, Tan reported. No treatment-related adverse events, including liver damage or elevation of inflammatory cytokines, were observed.

Based on these findings, the researchers conclude, "HBV DNA integration profile of tumour cells can guide personalized T cell adoptive immunotherapy of patients with HBV- related HCC."

"Further development of this new immunotherapeutic strategy may offer new hope of a cure for HCC," Tan said in a press release issued by the conference.