Engineered T-Cell Therapy and HCC - J of Hepatology. Jan 26

Engineered T-cell therapy is a precision immunotherapy approach designed to treat cancer by modifying a patient's T cells to enhance their ability to target and destroy cancer cells. This therapy involves genetic engineering of T cells to recognize tumor-associated antigens (TAAs) and improve their survival and function in the body. The most successful example of engineered T-cell therapy is chimeric antigen receptor-T cell (CAR-T) therapy, which has shown remarkable efficacy in treating hematological malignancies like refractory B-cell lymphoma/leukemia and multiple myeloma.

### Basis of Engineered T-cell Therapy in Hepatocellular Carcinoma (HCC)

Hepatocellular carcinoma (HCC) is a challenging cancer to treat using engineered T-cell therapy due to the complexities of solid tumors. These challenges include:

1. **Lack of Suitable Tumor-Associated Antigens:** Unlike hematological malignancies, HCC lacks well-defined and universally expressed TAAs that can be targeted effectively.

2. **Tumor Microenvironment:** HCC tumors create an immunosuppressive microenvironment characterized by hypoxia, immunosuppressive cells, and cytokines, which hinder T-cell activity.

3. **Tumor Stroma:** The dense stroma within solid tumors obstructs effective trafficking of T cells to the tumor site.

### Alpha-Fetoprotein (AFP) Targeting TCR-T Therapy in HCC

In a clinical trial reported by Meyer et al., researchers explored T-cell receptor (TCR)-T therapy targeting alpha-fetoprotein (AFP), a protein expressed in some HCC tumors. This therapy used ADP-A2AFP cells, which are engineered T cells designed to recognize AFP complexed with HLA-A*02:01. The trial enrolled 21 patients with AFP-expressing advanced solid tumors (20 with advanced HCC and 1 with gastric hepatoid carcinoma). The treatment involved lymphodepleting chemotherapy followed by infusion of the engineered T cells.

### Key Findings from the Trial:

1. **Safety and Adverse Events:**

• Dose-limiting toxicity was observed in one patient (grade 4 atrial fibrillation), who later died due to cholangitis unrelated to the therapy.
• Cytokine release syndrome (CRS) occurred in six patients, with one experiencing severe grade 4 CRS.
• Grade 3-4 leukopenia was observed in 10 patients, likely due to the lymphodepleting chemotherapy.

2. **Efficacy:**

• The overall response rate was 9.5%, with one complete responder and one partial responder.
• The trial highlighted difficulties in achieving satisfactory efficacy, partly due to variability in AFP expression among tumors and challenges in patient enrollment.

3. **Challenges:**

• Enrollment was limited due to the specific HLA haplotype required for the therapy and safety concerns associated with lymphodepleting chemotherapy in patients with cirrhosis.
• The prolonged time required for screening and cell preparation meant that only patients with slower tumor progression could participate.

### Lessons Learned and Future Directions:

1. **Tumor-Associated Antigen Variability:** The variability of AFP expression in tumors complicates the correlation between antigen expression and treatment efficacy. More precise diagnostic tools are needed to select patients who are likely to benefit from therapy.

2. **Improving T-cell Design:** Novel T-cell constructs or higher cell doses may enhance efficacy while maintaining safety.

3. **Targeting Multiple Antigens:** Engineering T cells to target multiple TAAs could improve specificity and reduce resistance due to antigen escape.

4. **Overcoming Tumor Microenvironment:** Strategies like incorporating interleukin-15 constructs or dominant-negative transforming growth factor-β receptors into CAR-T cells have shown promise in overcoming the immunosuppressive tumor microenvironment of HCC.

5. **Patient Selection:** T cells from less heavily pretreated patients may exhibit higher antitumor activity, and the phenotypes of engineered T cells should be optimized for trafficking and cytotoxicity.

### Advances in Engineered T-cell Therapy for Solid Tumors:

While engineered T-cell therapy for hematological malignancies has been highly successful, progress in treating solid tumors like HCC has been slower. Recent trials targeting glypican 3 (a membranous glycoprotein expressed in HCC) using CAR-T therapy have demonstrated promising antitumor activity and acceptable safety profiles. For example:

• CAR-T cells engineered with interleukin-15 constructs improved T-cell survival and function.
• CAR-T cells with dominant-negative transforming growth factor-β receptors helped overcome the immunosuppressive tumor microenvironment.

### Conclusion:

The clinical trial by Meyer et al. represents an important effort to develop precision immunotherapy for HCC. Although the efficacy of ADP-A2AFP therapy was limited, the study provides valuable insights into the challenges and opportunities in engineered T-cell therapy for HCC. Advances in cell engineering technologies and a better understanding of the interactions between engineered T cells, cancer cells, and the tumor microenvironment will be critical to driving progress in this field.