Beyond hematologic malignancies, adoptive therapy could potentially be effective in solid tumors, such as head and neck cancer, according to early results of a clinical trial.
Sophie Papa, MD
Sophie Papa, MD
Beyond hematologic malignancies, adoptive therapy could also potentially be effective in solid tumors, such as head and neck cancer, according to early results of a clinical trial presented at the 2017 AACR Annual Meeting.
In the dose-escalation phase I study, patients with head and neck squamous cell carcinoma were treated with T4 immunotherapy, which are T cells that are retroviral transduced to co-express T1E28ζ, a CAR coupling an ErbB ligand derived from EGF and TGFα to a fused CD28+CD3ζ endodomain, and 4αβ, a chimeric cytokine receptor containing the IL-4Rα ectodomain coupled to the IL-2Rβ endodomain.
While 90% of patients were lymphopenic, the T4 therapy was generated from a 130-mL blood draw in a closed manufacturing process. The authors noted, in the study, that batches contained up to 7.5 x 109cells, of which 63.8 +/- 12.1% were T4+. This comprised a variable mixture of central and effector memory CD4-positive and CD8-positive T cells. Cohorts of 1, 3, and 10 x 107 T4+ T cells were treated.
Results showed that the disease control rate was 44%, and all 3 patients in cohort 3 achieved stable disease. Regarding safety, treatment-related adverse events (AEs) were found to be grade 2 or lower, with no dose-limiting toxicities observed. The most commonly experienced AEs were tumor swelling or pain and fatigue.
In an interview withTargeted Oncologyduring the meeting, lead study author Sophie Papa, MD, medical oncologist, Clinical Academic Group, Department of Research Oncology, King’s College London, discusses the early-phase results and the logic behind studying CAR T-cell therapy in solid tumors, such as head and neck cancer.
TARGETED ONCOLOGY:Could you please provide an overview of the study being presented at this year’s meeting?
Papa:CAR T-cell therapy has really begun to become the standard of care in hematologic cancers that express CD19, and has made a huge impact on survival for patients with resistant, heavily pretreated cancers in that setting. What we are trying to do is use a CAR T-cell approach to treat a very different type of malignancy, head and neck squamous cell carcinoma.
Solid tumors pose [several] different challenges to CAR T-cell therapy. Some of the key ones we are trying to address with our protocol are, first and foremost, the fact that in the CD19 CAR T cells we are seeing, resistance is occurring, and the tumors are losing expression of the target CD19. Our approach uses a receptor that is based on the ligand that is able to interact with more than 1 receptor. Therefore, we are offering an approach that is hopefully going to overcome a degree of resistance in the tumor.
We are also trying to treat the patient population that carries a very heavy burden of comorbidities. The patients who suffer from head and neck cancer traditionally are older, frail, and have other comorbidities affecting their health. Using some of these approaches that have been instrumental in the success of CD19 CAR T-cell therapies opens up the risk of toxicity with cytokine release syndrome, neurotoxicity, etc, which is going to be harder to undertake in this patient population.
With the T4 trial, T cells are administered intratumorally rather than intravenously to try to target the activity where it’s needed in the locoregional disease, reduce the risk of the T cells getting into the circulation, and cause toxicity on targetbut off tumor. We are not lymphodepleting the patients to try and reduce the toxicities associated with this therapy.
Another fundamental difference in our approach compared with the other clinical trials that are ongoing with CAR T cells in different settings is that we do leukapheresis on the patients. We are able to use CAR 4αβ that we co-express with our CAR to manufacture cell product with a 100% success rate to date, from as little to 14 mL of whole blood to normally 120 mL of whole blood from our patients. We do this over a 14-day period.
TARGETED ONCOLOGY:Why is that manufacturing approach important?
Papa:Leukapheresis is expensive and it takes quite a long time. It potentially limits the rollout of this kind of technology at centers that are only able to do leukapheresis on patients. With our approach, it is just a blood draw; it’s less than what you would give when you’re donating blood out in the community. It enables us to take patients who are potentially quite lymphopenic and still manufacture cell product successfully from such a small starting material, which is going to be useful in the rollout of this technology.
TARGETED ONCOLOGY:What was the thought process in starting CAR T-cell research in head and neck cancer?
Papa:There are big challenges to taking this technology into solid tumors. One of the key challenges is that it’s very difficult to find something to target on a solid tumor that is only found on the tumor cells and not found on normal tissue. In reality, CD19, which is the target that CAR T cells have been particularly successful in to date, is not a tumor-specific antigen. We find that on all B cells from a very early B-cell evolution; but, it’s expendable. You can get rid of all CD19-expressing B cells in a patient with simple supportive measures.
In solid tumors, it is very difficult to try and find an antigen that is either tumor restricted or expendable, so we have to be cognizant of that and think of different approaches that enable us to take this technology safely into this patient population. That really underpins the whole approach when we begin to think about CAR T cells for head and neck squamous cell carcinoma.
TARGETED ONCOLOGY:What is the status of this trial?
Papa:It is a first-in-human phase I study. It’s a standard dose-escalation 3+3 design, and we have treated 3 dose cohorts to date. We have 2 more planned dose cohorts to reach our maximum deliverable dose using our manufacturing and intratumoral delivery approach. After that, all being wellif we haven’t experienced any significant toxicity—we are planning an expansion cohort with immune modulatory therapy.
TARGETED ONCOLOGY:What does the safety profile look like thus far?
Papa:The primary endpoint of this trial is dose-limiting toxicity, and to date we haven’t seen any toxicities that are dose limiting, which is great. We have seen 3 serious AEs, none of which have been related to therapy. All of the treatment-related AEs have been grade 2 or below, have only been seen in the highest-dose cohort, and have been manageable with simple supportive measures. This is a safe approach with minimal toxicity to date.
Pending positive results of this trial, what impact could this CAR T-cell therapy have on clinical practice in head and neck cancer?
One of the secondary endpoints is stable disease using RECIST version 1.1 criteria. All of the patients we recruited had progressive disease; the majority of patients were rapidly progressing on trial entry. We have a 63% disease control rate, so 5 out of 8 patients evaluable at 6 weeks had stable disease.
This is exciting. This is, essentially, nontoxic personalized therapy for patients with a very lethal form of cancer that appears to be controlling disease in the majority of patients. The future for this is to continue to dose escalate because we are really starting to see signs of more activity in patients in the higher dose level.
We need to continue to do it carefully to ensure that we don’t do harm in this patient population, and then combine this therapy with other immuno-oncology therapeutics that may enhance its efficacy. We are also looking to take the next step into a regional approach with CAR T cells, like the thoracic cavity in mesothelioma, or the abdomen peritoneal cavity for ovarian cancer. These are all potential approaches that we are planning.
Pappa S, Adam A, Metoudi M, et al. T4 immunotherapy of head and neck squamous cell carcinoma using pan-ErbB targeted CAR T-cells. In: Proceedings from the 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT118.