'Helper' T Cells effective in therapy, and shows early clinical responses in patients with metastatic cancer
Dr Yong-Chen William Lu - National Cancer Institute, Bethesda, USA
What happened in our phase I trial is we’ve been treating fourteen patients in the trial, eight patients doing a dose escalation and six patients at the highest dose. So far we have three responses, one at the dose escalation and the two other responses at the highest dose. For that we have one cervical cancer patient and one oesophageal cancer patient and lastly one urothelial cancer patient. Those patients have been doing well and, mostly importantly, since this is the first CD4 T-cell therapy we are glad to see these phase I studies being safe and we see some early response and we hope that in the phase II trial we can ask the question whether the response will stand to many different types of cancer.
What sets CD4 T-cells apart from CD8 killer T-cells?
There are two types of T-cell, one is CD4 T-cell or people call that the helper T-cell; another type of T-cell called killer T-cell, CD8 T-cell. So usually people think that the CD8 T-cell is in charge of the killing, to tumour cells and CD4 T-cells just provide the help. But today we want to ask the question whether CD4 T-cells alone not just provide help but also these cells can be in charge of the killing.
What pathways do the T-cells use to control cancer growth?
For scientists both in the clinical studies and also preclinical studies, we haven’t found a specific mechanism that induces that. So, so far we are seeing maybe one cytokine, it’s called interferon gamma, may play an important role in that but other than that it’s still very limited. So I think that the success of this clinical trial will help scientists and stimulate scientists to do more studies on the CD4 T-cell because, as we mentioned before, that we have a bias that CD4 T-cells only provide help but they maybe do much more than that.
What else were you discussing here at AACR 2016?
About the MAGE-A3, it’s one of the members of the antigen group is called cancer germline antigen. So that type of antigen is expressed during foetal development but when people grow up to adults that expression has been lost. So the only few places that those antigens will be expressed, one is in the germline cells and the other one is the tumour cell. So that’s why we chose that as a target because since it doesn’t express in the normal cells we avoid the dangers of targeting the T-cells against the normal cells.
Did it limit autoimmunity?
We don’t think so, we don’t think they have anything to do with autoimmunity in normal humans because normal tissues don’t express MAGE-A3.
What direction is your study heading in?
So far our major direction is to enrol patients from different cancer specimens, as long as they are MAGE-A3 positive. As we mentioned, we focussed on a few that are highly MAGE-A3 positive such as melanoma, oesophageal cancer, urothelial cancer and cervical cancer. So we try to ask the question whether this treatment will help those patients to have significant response and, most important, a long-term survival for those patients. Once we have that, that’s the first step, then the second step we’ll do is to find a different way to enhance the strength of the CD4 T-cell and then we may initiate a different trial to test those hypotheses.
What considerations are taken when targeting CD4 positive T-cells?
For the entire cancer immunotherapy field one of the important things is to choose the target. So, first, we think that MAGE-A3 is a good target and the second consideration is what type of approach we want to use – either use CAR or use TCR. Before that by default people thought just use CD8 T-cells, either use CAR or TCR, but now we have provided a new direction that people may like to try, which is the CD4 T-cell.
What dosage have you found to be most effective?
The dose that we used to define depends on the toxicity that we observed. So the design of the trial is we start with 10 million cells with one patient. If we observe any dose limiting toxicity we’ll stay with that dose and treat for six patients. Since we did not observe any toxicity, so that’s why we moved out to the highest dose and treated six patients to complete the study. So that’s the major purpose for the phase I study, it’s for safety. Then for the phase II then we’ll start the effectiveness and the efficacy for this trial. So at this time then we will start asking questions and just use the highest cell dose to do that.