The US firm AffyImmune Therapeutics discusses how its donor cell-derived candidate could address these issues.
CAR-T therapies have changed the game in the treatment of forms of blood cancer as they can provide longer-lasting benefits than chemotherapy. Approved CAR T therapies such as Carvykti and Abecma involve taking T cells from a cancer patient, genetically engineering them to fight cancer, and reinfusing them into the patient.
However, these therapies also face manufacturing and logistical bottlenecks that make them expensive to produce. So far, there are also no approved CAR-T therapies for taking on solid tumors.
AffyImmune’s lead candidate AIC100 is designed to treat advanced forms of thyroid cancer and targets a molecule on the cancer cell surface called ICAM-1. This so-called autologous CAR-T cell therapy is derived from donor T cells so has the potential to make it to cancer patients faster and more cheaply than current approaches.
Just before attending the 2024 annual meeting of the American Society of Clinical Oncology (ASCO), the Massachusetts-based company revealed that a patient had a complete response after receiving a dose of AIC100 in early results from a phase 1 trial. The company hailed the results as the first known complete response following a single intravenous dose of autologous CAR T cells in a solid tumor.
By the data cutoff point, the company had dosed 10 patients with up to 500 million CAR T cells. The rate of patients had a partial or complete response to the therapy, known as the overall response rate (ORR) was 33%. In terms of safely, six of the patients developed mild-to-moderate cytokine release syndrome, where the immune system reacts more aggressively to the therapy than it should. However, the investigators found no dose-limiting toxicities.
Biopharma Reporter spoke to AffyImmune CEO Matt Britz to get the breakdown of what the results mean for the company, and for the field of CAR-T therapy as a whole.
Can you explain what is driving the need for autologous cell therapies for cancer?
Today’s therapies are simply not curative. In our lead indication, advanced thyroid cancer, one approved therapy got that approval with a 2% complete response rate. These therapies are taken multiple times per day, often at reduced doses due to intolerable toxicities. The promise of a single-agent, single-dose, living drug with curative intent means a better quality of life for these patients.
Who are your main competitors and how does your therapy stand out?
Our main competitors include Iovance, which is developing a tumor infiltrating lymphocyte (TIL) for non-small-cell lung cancer and other CAR T cell therapy companies developing assets for solid tumor indications, like CARSgen and AbelZeta/AstraZeneca.
Our therapy stands out from TILs because of its relative ease of manufacturing – there is no biopsy required, and patients can generally have a lower tumor burden to participate in our study. Our study is run in US centers of excellence, and our responses to date have been durable, confirmed, and the result of one single dose of our drug product.
We're particularly excited about the safety profile of our autologous therapy, which does not include or require a suicide gene/switch. This durable metabolic complete response from a single-flat-dose, single-agent, systemically administered autologous CAR T is a first for the industry.
Why is it so important to see a complete response in a patient with anaplastic thyroid cancer from your phase 1 trial?
First and foremost, it’s a critically important outcome for the patient. Patients with anaplastic thyroid cancer live, on average, about six months from diagnosis. And in the six months since receiving our therapy, this patient has had no other anticancer therapy. No chemotherapy and no pills. It’s a quality of life that otherwise would not be available to patients who get this diagnosis.
For us as a company, it establishes a dose response between our second dose level, 100 million CAR T cells, where we had one patient with a partial response, and our third dose level, 500 million CAR T cells, which this patient received. That indicates to us that there may be value in pursuing even higher doses, and we’ve expanded our protocol accordingly based on our promising safety data.
When do you expect to complete your phase 1 study and launch further development of the candidate?
We expect to declare our recommended phase 2 dose later this year and open a pivotal phase 2 study in 2025.
What are the main challenges to developing autologous CAR T therapies and how are they being addressed?
The primary challenges for autologous CAR T today are safety, antigen loss – a mechanism by which a cancer cell can become resistant to CAR T therapy – exhaustion – where the CAR T cells lose their ability to proliferate and attack cancer – and access to patients. Through our affinity-tuned construct, we believe we’re addressing the safety and exhaustion issues.
Our selected target, ICAM-1, helps us address antigen loss; ICAM-1 is believed to be tumorigenic, so if it is downregulated by the tumor, the tumor should become less aggressive. What is further hypothesized, and recently published by the Maus lab at Massachusetts General Hospital over the past few years, is that ICAM-1 is actually upregulated as a downstream effect of a tumor defense mechanism involving the interferon gamma pathway. That means more antigen is available for binding, boosting the ability of AIC100 to bind to its target.
How do you see the CAR T field progressing in the next ten years?
Many in the field are looking at ways to solve the access problem. Manufacturing technologies that are faster and more scalable, including allogeneic platforms, may drive down cost of goods and eventually prices, for example.
Different modifications like armoring may improve CAR T cell performance, and cell therapies based on different cell types like natural killer cells, macrophages, or gamma delta T cells may be effective in certain hematologic or solid tumor indications. Taken together, all of these will be built on the foundation that autologous CAR T cells build over the next decade.
