At the American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting, Jo Brewer (VP Allogeneic Research, Adaptimmune) presented a poster detailing an update on using engineered specific peptide enhanced affinity receptor (SPEAR-T) cells to treat various solid tumors. In this interview, she discusses how this new data could help bring multiple, defined and consistent cell therapies for patients with cancer quickly and efficiently, which is crucial when treating late-stage metastatic cancers.
Q. What are the major challenges associated with using autologous T-cell products in cancer therapy?
Autologous cell therapies depend on harvesting a patient’s own cells, modifying them to attack cancer cells, expanding them, and then infusing them back into the patient. There are limitations to overcome with autologous cell therapies in terms of manufacturing and delivery. Working with patients’ own cells involves dealing with very varied quality of cells, because of previous treatments, complex scheduling between hospitals and manufacturing sites, and potentially long lead times. Many companies, including Adaptimmune, are working on an alternative cell therapy approach to overcome these challenges. This approach does not depend on harvesting a patient’s own cells and is called allogeneic or ‘off-the-shelf’ cell therapy. With an allogeneic product, one can produce a bank of modified cells that can be used, theoretically, by any eligible cancer patient. These cells would be manufactured, frozen and stored to be made available to patients as soon as treatment is needed.
Q. Could you give us an overview of the SPEAR T-cell platform?
Harnessing the power of the immune system to address cancer is a logical step as the immune system fights cancer all the time – whether we are aware of it or not. Adaptimmune’s SPEAR T-cell therapies are based on our proprietary technology that enables us to tune T-cell receptors or TCRs to recognize cancer targets. The immune system is naturally selected to avoid reacting to anything that looks like self and solid tumors often look like a patient’s own tissues. Although some T-cells are able to recognize cancer and fight it – these cells are rare. What we do is arm about 1 to 10 billion of a patient’s own T-cells with engineered TCRs to fight solid tumors. These engineered T-cell receptors or TCRs are specifically tuned against the cancer targets and we have seen large bulky tumors eliminated by our therapies across several cancer indications.
Q. What products are in development?
For our allogeneic program specifically, we have not given details yet about products that we will take into the clinic. We have recently announced that, as part of our partnership with Astellas, we have agreed the first collaboration program target for which the companies will develop an allogeneic HLA independent TCR (HiT) therapy. We will communicate more details when we are in a position to do so. We have conducted our allogeneic pre-clinical research using our ADP-A2M4 TCR, but we do not know yet if we will progress to the clinic with such a product. We have a pipeline of therapies in development including two first generation SPEAR T-cell therapies in clinical trials, ADP-A2M4 and ADP-A2AFP.
We have a third therapy in trial, called ADP-A2M4CD8, which is a next-generation SPEAR T-cell designed to improve on the potency of the first generation ADP-A2M4 treatment. This next-gen therapy aims to increase the effectiveness of CD4+ T-cells, thanks to a CD8α co-receptor expressed alongside the engineered TCR. We also have a rich research pipeline, including other next-gen modifications to increase the potency of our SPEAR T-cells, by overcoming tumor barriers, enhancing T-cell proliferation, and other approaches.
Q. What clinical studies are in progress and what have been the major findings to date?
For our allogeneic program, we are conducting pre-clinical research and are not at the clinical study stage. However, we aim to be in the clinic with our first allogeneic therapy as soon as we can. For our SPEAR T-cell therapies, our lead program called ADP-A2M4 is in a Phase 2 trial called SPEARHEAD-1, recruiting patients in synovial sarcoma and another type of sarcoma called MRCLS. We plan to launch this therapy in the US in 2022. We have seen compelling efficacy in synovial sarcoma, which is a difficult-to-treat cancer, in our Phase 1 trial with ADP-A2M4.
We initiated SPEARHEAD-1 based on data from our ADP-A2M4 trial conducted in 10 solid tumor indications, which has now completed enrolment, and we presented an update at ASCO on 29th May. In the ADP-A2M4 Phase 1 trial we are still running a sub-study investigating the combination of our product with low-dose radiation therapy to see if we can enhance responses as radiation may increase potency. Beyond sarcoma in this trial – we have also seen responses in head and neck cancer as well as melanoma.
Another trial we are conducting is SURPASS, the first trial with a next-generation version of the ADP-A2M4 therapy called ADP-A2M4D8. We have seen a response in three out of four patients dosed on this trial, two with gastro-esophageal cancer, leading us to start a Phase II study in that indication..
Finally have a trial with ADP-A2AFP in liver cancer. The first patient dosed with a dose of up to 5 billion cells in this trial has had a partial response.
Q. What are the company’s plans to develop the SPEAR-T cell platform in the coming year?
For our allogeneic program, we are continuing our pre-clinical work to bring it closer to the time when we can get a therapy in the clinic. We are also, in parallel, continuing to work with Astellas on the allogeneic HLA independent TCR (HiT) therapy that we plan to develop in collaboration. For our autologous SPEAR T-cells, we are delighted to have reported clinical responses in five solid tumors, with significant tumor reductions. These five indications include synovial sarcoma, head and neck cancer and melanoma with ADP-A2M4, gastro-esophageal cancer with ADP-A2M4CD8, and liver cancer with ADP-A2AFP. Screening for our SPEARHEAD-1 trial has been increasing in the first quarter of 2020. We intend for SPEARHEAD-1 to be used for registration, as we aim to launch our first therapy in the US in 2022. We continue screening and enrolling patients for our ongoing trials. We are close to starting a combination Phase 2 trial, called SPEARHEAD-2, combining ADP-A2M4 and pembrolizumab in head and neck cancer. And of course, we will be looking for new indications to move into Phase 2 trials, depending on data we report in ongoing trials.
Disclosure: Jo Brewer has no conflicts of interest to declare in relation to this interview.
Support: Interview supported by Touch Medical Media, who commissioned the interview in liaison with Evoke KYNE.
Published: 2 June May 2020