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Friday, March 4, 2022

Clinical Safety and Efficacy of Locoregional Therapy Combined with Adoptive Transfer of Allogeneic γδ T Cells for Advanced Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma

Clinical Safety and Efficacy of Locoregional Therapy Combined with Adoptive Transfer of Allogeneic γδ T Cells for Advanced Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma


Clinical question
Is locoregional therapy plus adoptive transfer of allogeneic gamma delta (γδ) T cells safe and effective in treating patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC)?

Take-away point
The combination of both locoregional ablation and adoptive transfer of allogeneic γδ cells is both safe and effective in patients with HCC and ICC.

Reference
Zhang T, Chen J, Niu L, et al. Clinical safety and efficacy of locoregional therapy combined with adoptive transfer of allogeneic γδ t cells for advanced hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Journal of Vascular and Interventional Radiology. 2022;33(1):19-27.e3.

Click here for abstract

Study design
Randomized Controlled Trial

Funding source
This study was funded by grants from the National Key R&D Program of China (2018YFA0108304), National Natural Science Foundation of China (81771721, 81971505), and Fujian Provincial Health Education Joint Research Project (WKJ2016-2-20).

Setting
Single institution, Fuda Cancer Hospital of Jinan University, Guangzhou, China


Figure 5. Survival curves. Overall survival curves of hepatocellular carcinoma (HCC) patients (a). Distant progression-free survival (PFS) curves of HCC patients (b). Local PFS curves of HCC patients (ablation sites) (c). Overall survival curves of intrahepatic cholangiocarcinoma (ICC) patients (d). Distant PFS curves of ICC patients (e). Local PFS curves of ICC patients (ablation sites) (f).

Summary


Adoptive transfer of T cells has emerged as a novel treatment of malignant neoplasms. A subset of T cells known as γδ T cells has been specifically utilized to recognize and eliminate tumor cells based on tumor-specific antigens. In an allogeneic adoptive transfer strategy, the γδ T cells are provided by a donor, amplified in vitro, and subsequently infused into a patient with a known cancer (as supposed to in vivo activation by zoledronate and IL-2). Few clinical trials have been conducted in patient populations with advanced disease due to the larger tumor burden and associated immunosuppressive environment. It is postulated by the authors that the combination of locoregional ablative therapy in concert with systemic treatment using allogeneic γδ T cells may be an effective treatment. 

Cryoablation and irreversible electroporation (IRE) are locoregional therapies that have proven efficacy and safety, while also preserving tumor cell surface architecture to potentially allow immune system recognition and subsequent response. Thus, the merit behind combining these modalities with systemic immune therapy is evident. Additionally, adoptive transfer has been shown to be safe and effective in several late-stage cancers as a monotherapy as well as in combination with IRE, and infused γδ T cells are known to preferentially migrate to the liver. Thus, a study of the safety and efficacy of a combination of locoregional therapy and adoptive transfer in the treatment of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) was devised.

In this randomized controlled trial, patients between the age of 18-75 years of age with stage III or IV HCC or ICC by 7th AJCC TNM guidelines were included. The study also required patients have multifocal disease that made them unsuitable for surgery or chemotherapy. They could not have tumor invasion of the portal vein, hepatic vein trunk, or secondary branches, and had to have a projected survival of > 3 months. Additional inclusion criteria included Eastern Cooperative Oncology Group (ECOG) performance status (PS) score ≤ 2, normal laboratory parameters, and adequate hepatic and renal function. Patients with coagulation disorders, anemia, severe coronary artery disease, respiratory disease, myelosuppression, acute or chronic infection, or autoimmune disease were excluded. Patients were randomized to either the combined treatment or local treatment groups using a computer-generated random number table. Patients in the combined treatment group underwent either IRE or cryoablation followed by adoptive transfer of allogeneic γδ T cells. Patients in the local treatment group only underwent either IRE or cryoablation. IRE was used for tumors adjacent to large vessels such as the hepatic artery, portal vein, or bile ducts in the liver hilum. Other tumors were treated with cryoablation. Additionally, transarterial chemoembolization was done prior to ablation on tumors > 5 cm in size to reduce tumor size prior to locoregional therapy. In patients undergoing adoptive transfer, donor γδ cells were collected, isolated, and expanded as previously described in the literature on day 1 of treatment. The patients then underwent locoregional therapy on day 9 before receiving donated cells in 3 equal infusions, with one each on days 13, 14, and 15. This was followed by a 2nd donation on day 16 and infusions on days 28, 29, and 30. Additionally, peripheral blood was drawn on day 8 and a month after day 30 to determine CTC levels. Follow-ups included CT or MRI at 1 month and every 3 months after treatment. These were compared to imaging collected 1 week prior to locoregional therapy. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was used to evaluate treatment response. Technical success was defined as complete ablation while local progression was defined as reappearance of arterial phase enhancement of the ablated area after initial technical success. Distant progression was defined as the appearance of new intrahepatic or extrahepatic tumors or an increase of over 20% in diameter of any unablated tumors. Overall survival was defined as time between locoregional therapy and death. Additional primary endpoints included safety (adverse events), distant progression-free survival (PFS), and local PFS. Secondary endpoints were CTC levels, AFP and CA19-9 (for HCC and ICC respectively), and change in ECOG PS.

Median survival was improved in the HCC group undergoing combination therapy compared to locoregional therapy, with median OS being 13 months for combination and 8 months for locoregional therapy, 1-year OS rates of 57.3% and 7.3% respectively, and 2-year OS rates of 26.7% and 7.3% respectively (p = 0.029). Median distant PFS in combination and locoregional were 8 and 4 months, with 1-year distant PFS rates of 0% and 21.8%, respectively (p = 0.040). Differences in local PFS rates were not significant (p = 0.949, 28.6% in combination group and 14.5% in locoregional group).

For patients with ICC, differences in OS were not significant; median OS was 9 months for combination and 8 months for locoregional therapy, 1-year OS rates of 33.3% and 44.3% respectively and 2-year OS rates of 25% and 8.3% respectively (p = 0.546). Median distant PFS in combination and locoregional groups were 8 and 4 months, with 1-year distant PFS rates of 14.1% and 0%, respectively (p = 0.021). Similar to HCC groups, differences in local PFS rates were not significant (p = 0.394, 16% in combination group and 27.5% in locoregional group). The authors mention that 28.6% of ICC patients and an unspecified number HCC in their respective combination groups did not receive locoregional therapy and dropped out of the study due to progression or withdrawal of consent, prompting a protocol analysis. The results of the protocol analysis were reported as consistent with the intention-to-treat (ITT) analysis.

AFP decreased in all groups, with a more pronounced drop in the combined treatment groups (HCC: p = 0.046, ICC: p = 0.028). Change in CA-19-9 was not significantly different between the experimental and control groups. CTCs decreased in all groups, but was more pronounced in the combined treatment groups (HCC: p = 0.035, ICC: p = 0.003). ECOG PS improvements were also statistically significant in both combined treatment groups (HCC: p = 0.039, ICC: p = 0.007), whereas the locoregional groups did not significantly change after treatment.

No severe adverse events occurred during this study. Only grade 1 and 2 events were reported, with most being grade 1 (least significant). These included fever, nausea, thrombocytopenia, arrhythmia, hemothorax, pneumothorax, pleural effusion, and fatigue. The majority of these were grade 1 and all adverse events were resolved spontaneously or with symptomatic treatment. Most events were associated with locoregional therapy, and there was no significant difference in incidence between the two groups. There was no significant difference in lab markers for hepatic or renal function.

Commentary


This study aimed to demonstrate safety and explore hypothesized efficacy of adoptive transfer of healthy volunteers' (allogeneic) γδ T cells in combination with locoregional therapies in the treatment of advanced HCC and ICC. This was done by employing previously-described techniques and timelines that have been proven safe and modestly effective. Results of this study demonstrated statistically significant if modest improvements in distant PFS for both HCC and ICC patients, but no differences were seen in local PFS. Additionally, OS was improved after combination therapy for HCC patients, but not for ICC patients. It is supposed that the lack of difference in local PFS is due to the primary contribution of locoregional therapy to this metric in all groups. Despite this, PS did improve in both combination groups while not in locoregional groups. It is hard to say, however, if this is clinically significant. The authors also posited that the significantly pronounced decrease in CTCs in both combination groups was likely secondary to systemic effects of γδ T cells and also likely the reason for the differences in distant PFS. Indeed, decrease in CTCs is a previously-demonstrated effect of γδ T cell infusion, and is known to be associated with increased PFS as well as impaired metastasis and recurrence. The decrease in AFP in HCC patients with combination therapy and the respective lack of decrease in CA19-9 in ICC patients, in concert with the less-pronounced survival differences in ICC patients, further suggests that combination therapy may be less effective in treating ICC. ICC is also acknowledged as a morbid diagnosis that progresses rapidly, is refractory to first-line treatments, and is often diagnosed in advanced stages, and thus may require a larger sample to determine true efficacy. 

While this trial was an RCT, it does have some limitations. One is that a higher proportion of patients in the combination groups did not undergo intended therapy. Although the PP and ITT analyses were consistent, this still may affect true therapeutic effect. Additionally, the study was open-label without allocation-concealment, which undermines the randomization design. Finally, the use of both IRE or cryoablation, with their different utilities and mechanisms of action, may have resulted in unknown effects on the data. Future trials will benefit from larger sample size, standardization of locoregional therapy or subgroup analysis of the modalities used, and double-blinding to ensure randomization.

Post Author
Jared Edwards, MD
General Medical Officer
Medical Readiness Division
Naval Surface Forces Pacific, San Diego, CA
@JaredRayEdwards

Edited and formatted by @NingchengLi
Interventional Radiology Resident
Dotter Institute, Oregon Health and Science University

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