Clinical Trials Update

Specific Peptide-Enhanced Affinity Receptor T cells for Hepatocellular Carcinoma

AFPc³³²T in Advanced HCC is a phase 1, open-label, first-in-human clinical trial to evaluate the safety and anti-tumor activity of genetically engineered affinity-enhanced autologous T cells that target the HLA-A*02-restricted alpha-fetoprotein peptide for the treatment of adults with relapsed or refractory HCC.

Researchers are currently enrolling patients into the study; eligible participants will have their T cells harvested and sent to the manufacturer for genetic modification. Patients will then receive infusions of autologous AFPc³³²T (SPEAR T-cells; Adaptimmune) after an approximate 4- to 6-week manufacturing period.

Lipika Goyal, MD
Lipika Goyal

Cell Therapy Next recently spoke with Lipika Goyal, MD, a gastrointestinal medical oncologist specializing in hepatobiliary cancers at Massachusetts General Hospital Cancer Center and one of the trial’s principal investigators, for an update on its progress, the interventional strategy and to discuss who is eligible to enroll.

Q: What was the rationale behind conducting this trial?

The median survival for patients with advanced HCC is one year, and there is a considerable unmet need in having therapies that provide blockbuster responses or that can even just prolong survival. Several drugs have been approved for this cancer since 2007, but we are still looking for drugs that will have a lasting impact and ones that will transform the treatment of this cancer.

Q: Why does HCC have a poor response to currently approved treatments?

First, it’s a very molecularly heterogenous disease; and, second, it usually comes with comorbid cirrhosis. Both of these impact the limits of any single agent.

Q: What makes the AFPc³³²T cells you are using novel compared with previous treatments for HCC?

We use the patient’s own T cells and modify them to recognize the cancer as foreign. We infuse these T cells into the patient so they can home in on and attack the cancer cells. It’s a very personalized medicine approach in a disease where there are no similar approved treatments.

Q: How does this treatment address the issue of treatment toxicities associated with previous cell-based immunotherapies?

The main concern that we had with this drug was that, given it targets AFP, it may have an effect on the non-cancerous portion of the liver. But so far, we are happy with the results. We have treated two patients to date with no liver toxicity, nor have we seen any significant neurotoxicity or cytokine release syndrome in either of these patients.

Q: What has been the response to therapy so far?

Both patients were safely treated — and we are very happy about that. One patient had stable disease for 12 weeks and both scans and on-treatment biopsy showed some degree of tumor necrosis. The second patient had stable disease at 4 weeks, but subsequently progressed and moved on to additional therapy.

Q: What is the treatment process?

First, we do the apheresis to harvest the patient’s T cells so they can be modified to express the AFP TCR. Then we bring patients to the hospital for conditioning with a couple of days with fludarabine and cyclophosphamide. We then infuse the modified cells into the patient and monitor them in the hospital before they are eventually discharged.

US Liver Cancer Cases

Q: What are some of the important inclusion criteria for patients with refractory HCC who might be eligible for this trial?

They must have a specific HLA type (HLA-A*02:01 or HLA-A*02:642 allele) and have either AFP expression on their tumor or high serum levels of AFP.

Q: How do you approach the topic of participating in a trial like this for those who may be eligible?

I explain to them the currently available standard therapies and let them know that we are always trying to improve outcomes for patients with HCC. I tell them this is a novel approach that potentially gives people better outcomes than with treatments that are currently available, but this is a research trial, so we don’t yet know the safety and efficacy of the treatment. If they want to try something new that has good scientific rationale behind it, then I explain that this may be a good option.

Q: How much promise does a novel therapy like this hold for the treatment of solid tumors, such as HCC?

Trial information

We are very hopeful. It’s nice that AFP is a relatively specific target for HCC.

We have made strides with T cell therapies in liquid tumors [hematologic cancers] but not as much in solid tumors, so we are hoping that this will be one of the therapies that forges the way in solid tumors. – by Drew Amorosi

Disclosure: Goyal reports being a consultant/advisory board member for Agios Pharmaceuticals, Debiopharm, H3 Biomedicine, Pieris Pharmaceuticals and Taiho Pharmaceuticals.

AFPc³³²T in Advanced HCC is a phase 1, open-label, first-in-human clinical trial to evaluate the safety and anti-tumor activity of genetically engineered affinity-enhanced autologous T cells that target the HLA-A*02-restricted alpha-fetoprotein peptide for the treatment of adults with relapsed or refractory HCC.

Researchers are currently enrolling patients into the study; eligible participants will have their T cells harvested and sent to the manufacturer for genetic modification. Patients will then receive infusions of autologous AFPc³³²T (SPEAR T-cells; Adaptimmune) after an approximate 4- to 6-week manufacturing period.

Lipika Goyal, MD
Lipika Goyal

Cell Therapy Next recently spoke with Lipika Goyal, MD, a gastrointestinal medical oncologist specializing in hepatobiliary cancers at Massachusetts General Hospital Cancer Center and one of the trial’s principal investigators, for an update on its progress, the interventional strategy and to discuss who is eligible to enroll.

Q: What was the rationale behind conducting this trial?

The median survival for patients with advanced HCC is one year, and there is a considerable unmet need in having therapies that provide blockbuster responses or that can even just prolong survival. Several drugs have been approved for this cancer since 2007, but we are still looking for drugs that will have a lasting impact and ones that will transform the treatment of this cancer.

Q: Why does HCC have a poor response to currently approved treatments?

First, it’s a very molecularly heterogenous disease; and, second, it usually comes with comorbid cirrhosis. Both of these impact the limits of any single agent.

Q: What makes the AFPc³³²T cells you are using novel compared with previous treatments for HCC?

We use the patient’s own T cells and modify them to recognize the cancer as foreign. We infuse these T cells into the patient so they can home in on and attack the cancer cells. It’s a very personalized medicine approach in a disease where there are no similar approved treatments.

Q: How does this treatment address the issue of treatment toxicities associated with previous cell-based immunotherapies?

The main concern that we had with this drug was that, given it targets AFP, it may have an effect on the non-cancerous portion of the liver. But so far, we are happy with the results. We have treated two patients to date with no liver toxicity, nor have we seen any significant neurotoxicity or cytokine release syndrome in either of these patients.

Q: What has been the response to therapy so far?

Both patients were safely treated — and we are very happy about that. One patient had stable disease for 12 weeks and both scans and on-treatment biopsy showed some degree of tumor necrosis. The second patient had stable disease at 4 weeks, but subsequently progressed and moved on to additional therapy.

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Q: What is the treatment process?

First, we do the apheresis to harvest the patient’s T cells so they can be modified to express the AFP TCR. Then we bring patients to the hospital for conditioning with a couple of days with fludarabine and cyclophosphamide. We then infuse the modified cells into the patient and monitor them in the hospital before they are eventually discharged.

US Liver Cancer Cases

Q: What are some of the important inclusion criteria for patients with refractory HCC who might be eligible for this trial?

They must have a specific HLA type (HLA-A*02:01 or HLA-A*02:642 allele) and have either AFP expression on their tumor or high serum levels of AFP.

Q: How do you approach the topic of participating in a trial like this for those who may be eligible?

I explain to them the currently available standard therapies and let them know that we are always trying to improve outcomes for patients with HCC. I tell them this is a novel approach that potentially gives people better outcomes than with treatments that are currently available, but this is a research trial, so we don’t yet know the safety and efficacy of the treatment. If they want to try something new that has good scientific rationale behind it, then I explain that this may be a good option.

Q: How much promise does a novel therapy like this hold for the treatment of solid tumors, such as HCC?

Trial information

We are very hopeful. It’s nice that AFP is a relatively specific target for HCC.

We have made strides with T cell therapies in liquid tumors [hematologic cancers] but not as much in solid tumors, so we are hoping that this will be one of the therapies that forges the way in solid tumors. – by Drew Amorosi

Disclosure: Goyal reports being a consultant/advisory board member for Agios Pharmaceuticals, Debiopharm, H3 Biomedicine, Pieris Pharmaceuticals and Taiho Pharmaceuticals.