Targeting CD8 T-cells and Using PET Imaging
ImaginAb’s drug, 89Zr-Df-Crefmirlimab, uses the radioactive metal Zirconium-89 (89Zr) attached to a minibody biologic. The team decided to target CD8 T-cells because they are associated with desirable prognostic outcomes in many cancer indications: “If the tumour has lots of CD8 T-cells, [the patient] is more likely to respond to immunotherapy.”
Their minibody biologic is about half the size of a full-sized antibody and has a high affinity to the CD8α chain. Its small size means it reaches the target site very quickly after injection. The isotope 89Zr has a half-life of around three days, and the product has a shelf life of six days, which is long enough to centralise manufacturing and distribution.
Although the drug is still an investigational product, “the compound is intrinsically inert,” says Wilson. The FC regions of the minibody have been removed, which makes it effectively a passive carrier; it doesn’t affect the T-cells in the body at all. Therefore, it has been deemed safe to use in clinical trials by regulatory authorities like the FDA.
Figure 1 – Using ImmunoPET, images can display areas of strong CD8 T-cell activity. Dark regions indicate this activity.
Figure 1 shows four scans taken one hour to six days after injection. The darker areas of the image are regions in the body that are highly associated with CD8 T-cells: the spleen, lymph nodes, and bone marrow, as well as a tumour indicated with green arrows.
Three ImmunoPET Case Studies
Wilson demonstrated the advantage of CD8 ImmunoPET by considering three patients given checkpoint inhibitors (shown left to right in Figure 2).
Figure 2 – Three examples of CD8 ImmunoPET use in cancer patients. Bright red spots show CD8 T-cell activity.
Wilson described a “doughnut” of CD8 activity around the tumour in the first example before treatment (top left). This indicates that the T-cells are surrounding the tumour but cannot enter it. After a cycle of checkpoint inhibitors, the PET scan clearly shows that those cells can penetrate the tumour site (bottom left). This indicates that the patient responded to treatment.
The second example (middle row) shows an immunosuppressed patient. Before treatment (top middle), there are very few CD8 cells at the tumour site. After treatment (bottom middle), the trend continues. There is still very little T-cell activity, and the tumour has increased in size, which indicates that the patient is not responding to the treatment.
Wilson’s final example demonstrates an advantage of the ImmunoPET technology. It shows no significant change in CD8 activity around the tumour site after treatment (bottom right). However, a noticeable increase in intensity at the mediastinal lymph node suggests that the therapy has redistributed the T-cells to the lymph node and not the actual tumour.
Herein, ImmunoPET can alert clinicians if the treatment is ineffective and why it may be ineffective. Wilson says that this may mean that clinicians may want to continue the treatment in this case and wait to see if there is a change in response.
How can CD8 ImmunoPET be used in clinical development?
The advantage of CD8 ImmunoPET is it allows clinicians to define the CD8 status within the tumour microenvironment and the rest of the body. This allows you to classify patients’ tumours into hot, cold, and immune-excluded categories after treatment which is highly beneficial in clinical trials.
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You can also stratify those patients before a clinical trial and define them into different cohorts. For example, the trial could observe treatment in patients with a high CD8 status against a cohort with low CD8 status, providing more valuable data to the trial.
The technology additionally has excellent potential for selecting the most optimal sites on which to perform different treatments, such as intertumoral therapy, radiotherapy, and biopsy. All the while, ImmunoPET can help optimise dosing, parallel and sequence multitherapy, and quick identification of early responders to treatment.
Wilson demonstrates how ImmunoPET can be an invaluable tool for conducting clinical trials for immunotherapeutic treatments. Therefore, the technology has the potential to elevate the speed and direction of clinical candidates’ translation into the clinic.
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