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Feun et al. Immunotherapy for hepatocellular carcinoma

FUTURE DIRECTION tremelimumab has been combined with subtotal
ablation (TACE, RFA or cryoablation) in patients
Immunotherapy, especially checkpoint inhibitors, with either HCC or biliary tract carcinomas. [41] In this
has recently shown promise in a number of study 14 patients had TACE, 19 had RFA, including
cancers, including HCC. How to improve current 9 with biliary tract cancers and 5 had cryoablation.
immunotherapy for HCC? Understanding the No dose limiting toxicity was noted during the trial.
mechanisms of resistance and methods to potentiate Seventeen patients were evaluable for response
response remain a challenge. It has been shown that for lesions outside of TACE/RFA-treated lesions.
intrahepatic HCV-specific CD8 T-cells from patients Of these 4 patients or 23.5% had confirmed partial
with chronic HCV infection were highly PD-1 positive, response. This is noteworthy that 10 of 12 patients
very dysfunctional, and unexpectedly refractory to with quantifiable HCV had marked reduction in viral
PD1/PD L-1 blockade. [37] This functional impairment load. Liver biopsies were done at week 6. These
was HCV-specific and directly correlated with the showed increase in CD8+ T-cells only in patients with
level of PD-1 expression. The highly PD-1 positive clinical response. Furthermore, in peripheral blood
intrahepatic CD8 T-cells were more exhausted with mononuclear cells, there was a statistically significant
increased CTLA-4 and with reduced CD28 and CD change in CD4/T reg and CD8/T reg ratio in clinical
127 than circulating T-cells. Thus, a novel therapeutic responders. The median time to tumor progression for
approach is to combine CTLA-4 with PD-1 blockade. evaluable HCC patients was 5.7 months. [41]
Indeed, studies have shown that there is a synergistic
reversal of intrahepatic HCV-specific CD8 T-cell Chemotherapy has been used for lymphodepleting
exhaustion by combining anti-CTLA-4 antibody with prior to adoptive T-cell therapy. This lymphodepletion
PD-1 inhibitor. [38] This has therapeutic implications as has been shown to enhance immune reconstitution
both anti-CTLA-4 antibody and PD-1 inhibitors alone by the transferred cells and increase tumor specific
have shown activity in HCC. [30-32] As demonstrated responses. Low dose cyclophosphamide can impair T
in the treatment of malignant melanoma, the regulatory cells and can unmask AFP- specific CD4+
combination has been tolerable and antitumor T-cell responses in patients with advanced HCC. [12]
response may be greater than single agent used Adoptive T-cell therapy itself, which uses a patient’s
alone. However, toxicities including more autoimmune own T lymphocytes genetically altered to enhance
reactions such as diarrhea, hypophysitis and hepatitis anti-tumor activity, expanded in vivo and then infused
may be more frequent and the dose and tolerability of into the patient, has a number of problems. Problems
combination therapy will need to be carefully defined. include the need for surgery to obtain tumor-reactive
Drug-induced hepatitis is the main concern and may TIL cells and the expansion of the TIL cells from
limit patients with significant liver impairment including tumors. Alternatively, adoptive transfer of bulk T
those with a history of autoimmune diseases such as lymphocytes can be procured from peripheral blood
autoimmune hepatitis. and expanded in vivo to generate large number of
T lymphocytes before infusing back into the patient.
Currently, a study is being planned to combine anti- Problems with this approach include tumor cells
CTLA-4 antibody with anti-PD-1 inhibitor in advanced, can have low antigen presentation and most tumor
unresectable HCC. antigens are normally expressed as self-antigens.
Thus, the T-cell receptor (TCR) may have low affinity
Another approach is to apply different modalities for these self-tumor antigens.
together. There is a rationale to evaluate combinatorial
therapy for HCC. Adding checkpoint inhibitor to TACE To overcome these obstacles, T-cells have been
or liver ablation seems reasonable. TACE and liver genetically engineered to stably express transgenes
ablation can both increase T-cell infiltration including using viral transduction, often with vectors from
NK cells. [7,39] Another study showed that CD4/CD8 gamma retroviruses or lentiviruses. Molecularly
ratio and number of B cells and natural killer cells engineered TCRs have certain advantages including
were significantly decreased in HCC patients prior to the ability to target all cellular proteins and not just
treatment. [40] When compared to pretreatment levels, cell surface epitopes. Genetically altering the T-cells
the CD4+ and CD4/CD8 ratio decreased but the to express a tumor antigen specific TCR is one way
CD8+ cells increased in the TACE group. In the TACE to target a specific tumor antigen (chimeric antigen
+ RFA group, the CD4/CD8 ratio and the natural killer receptor-T-cells or car-T-cells). TCR engineered T-cell
cells and the CD8+ cells increased. On the other transfer using human TCRs targeting AFP is currently
hand, the CD3+, CD8+, CD4/CD8 ratio and natural in clinical trial in several institutions, including our
killer cell increased in the RFA group. More recently, Center. Known toxicities to this approach include
Hepatoma Research ¦ Volume 3 ¦ March 22, 2017 47