PharmaShots Interview: Adaptimmune's Dennis Williams Shares Insight About the Company's Pathway to Bringing the First-Ever TCR T-Cell Therapy for Solid Tumors to Market

In an interview with PharmaShots, Dennis Williams, SVP Late-stage Development at Adaptimmune shared his views on the Company's unique SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell platform and their pathway to bringing the first-ever TCR T-cell therapy for solid tumors to market along with an overview about their industry-leading T-cell therapy pipeline in solid tumors.

Adaptimmune develops novel cancer immunotherapy products for people with cancer and its unique SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell platform enables the engineering of T-cells to target and destroy cancer across multiple solid tumors
P-II SPEARHEAD-1 is a trial for people with advanced synovial sarcoma or MRCLS to evaluate afami-cel targeting MAGE-A4+ tumors with convincing clinical responses reported previously
SPEAR T-cell therapies targeting MAGE-A4, and AFP are rolling through clinical studies in multiple solid tumors while the clinical studies for SPEAR T-cell therapies targeting MAGE-A10 have been closed

Tuba: Highlight the key points of P-II SPEARHEAD-1 trial data presented at ASCO.

Dennis:

People with synovial sarcoma and MRCLS have very limited treatment options
The data we presented at ASCO from our SPEARHEAD-1 trial represents a game-changer for people with these types of cancer
We presented data from 33 evaluable patients who had received afami-cel and there was an overall response rate of 39% with two patients having complete responses
The disease control rate, meaning patients have either responses or stable disease, was 85%
These response rate results are better than any currently available 2nd line treatments
We also showed data indicating that afami-cel has been safe and well-tolerated, with mainly low-grade cytokine release syndrome and manageable hematologic toxicities
We plan to use these data to support our BLA filing next year

Tuba: What is afamitresgene autoleucel? Discuss its MOA.

Dennis:

At Adaptimmune, we are leaders in designing and engineering T-cell receptors or TCRs to target solid tumors
Afamitresgene autoleucel or afami-cel is an engineered TCR T-cell therapy product designed to target solid tumors
We can engineer TCRs to target proteins expressed inside cells and this is a distinct advantage with solid tumors because they lack unique cell-surface proteins
In the case of afami-cel, this TCR is specifically engineered to target a tumor antigen called MAGE-A4 that is expressed in a broad range of cancers, including synovial sarcoma
To make afami-cel, we harvest a patients own T-cells via a process called apheresis
These T-cells are shipped to our manufacturing facility where we genetically modify them to express the enhanced TCR targeting MAGE-A4
We expand the modified T-cells, test them, and freeze them to send back to the patient for infusion
The patient undergoes a process called lymphodepletion to make room for the MAGE-A4 targeted T-cells or afami-cel product to expand
When the patient is ready, they receive their genetically modified T-cells to fight cancer
It is a 'one and done' therapy, unlike chemotherapy or radiation that require multiple treatments
We have had patients tell us that our cell therapies have given them their lives back because they have been freed from frequent hospital trips to receive multiple rounds of chemo or radiation

Tuba: When are you expecting the first approval of the company? Can you draw us a roadmap for application & approval for our readers?

Dennis:

We want afami-cel to be the first engineered TCR T-cell product approved in a solid tumor indication. More simply put, our goal is to make a difference for people suffering from sarcoma and to make afami-cel available to as many patients as we can.
We are on track to file our first Biologics License Application or BLA with the US FDA next year for the approval of afami-cel for people with synovial sarcoma or MRCLS. We will file this application based on data from our Phase 2 SPEARHEAD-1 trial as well as data from our Phase 1 trial with afami-cel
Previously, we received several key regulatory designations based on data from patients with synovial sarcoma in our Phase 1 trial with afami-cel: RMAT in the US and PRIME in the EU, and orphan drug designation in both regions. These designations are important for 2 reasons
- First, they provide external validation of the clinical data. Regulatory designations such as the Regenerative Medicine Advanced Therapy Designation, or RMAT, the European Orphan Drug Designation, or the European Medicines Agency Priority Medicines Scheme or PRIME, require clear clinical evidence, demonstrating the ability to either address an unmet medical need or some advantage over available therapies. Only promising therapies receive these designations.
- Second, these designations enable expedited drug development through several incentives. These incentives include expedited reviews of marketing applications and enhance interactions with regulatory authorities, including formal meetings.
In addition to these regulatory designations, the clinical evidence from the Phase I trial allowed us to initiate the Phase 2 SPEARHEAD-1 trial. The data from SPEARHEAD-1, recently presented at ASCO and to be updated later this year at CTOS, further strengthen my confidence that afami-cel will be the first TCR T-cell therapy approved for a solid tumor indication.

Tuba: Discuss the Company's pathway to bring the first-ever TCR T-cell therapy for solid tumors to market?

Dennis:

It is our ambition to file for approval next year for afami-cel. Time to market will depend on our interactions with FDA and other regulatory authorities after filing
In addition to our regulatory preparations for filing our first BLA, we have also initiated several early commercial activities.
These have included optimizing our patient journey in collaboration with patient advocacy groups, such as the Sarcoma Foundation of America.
We've conducted some initial sarcoma market sizing. And we've had an engagement in early scientific advice with U.S. payers and health technology assessment bodies to generate insights on payer evidence requirements.
We are also a fully integrated cell therapy company with our cell manufacturing facility with the capacity to meet the demands for our ongoing clinical trials as well as for people with synovial sarcoma and MRCLS if we receive marketing approval

Tuba : What are the other indications in which you are evaluating the ADP-A2M4?

Dennis:

MAGE-A4 represents a tremendous opportunity as a cancer target and we aim to identify new indications for late-stage development from our ongoing trials
Our first-generation product targeting MAGE-A4 was called ADP-A2M4, now afami-cel
We also have a next-generation product targeting MAGE-A4 that uses the same TCR as afami-cel, with the addition of a CD8 alpha co-receptor (ADP-A2M4CD8) designed to increase potency
We have reported clinical responses in several MAGE-A4 expressing cancers, beyond sarcoma, with afami-cel or ADP-A2M4CD8 including melanoma, lung, head and neck, and esophagogastric junction (EGJ) cancers
- We are currently enrolling patients in our SURPASS trial with our next-generation product targeting MAGE-A4 with a focus on lung, gastroesophageal, head and neck, and bladder cancers all indications where we have seen signs of efficacy with our MAGE-A4 targeted T-cells. We plan to identify additional indications for late-stage development from this trial
We also intend to initiate a Phase 2 trial, SURPASS-2, with ADP-A2M4CD8 for people with EGJ and esophageal cancers, which could form the basis of a second approval

Tuba: Discuss the company's SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell platform. How it is revolutionizing cancer therapies?)

Dennis:

SPEAR stands for Specific Peptide Enhanced Affinity Receptor and this refers to the proprietary technology that enables us to engineer T-cell receptors or TCRs to optimally target and kill cancer cells
Solid tumors often evade the immune system because cancer looks a lot like the body's own cells
Every protein in the body is broken down and fragments -- called peptides -- are presented on the surface of body cells in antigen presentation molecules called human leukocyte antigen or HLA. The HLA:peptide complexes are surveyed by T-cells looking for evidence of foreign proteins such as those from viruses
When T- cells recognize a peptide:HLA complex with the right binding strength, indicating that the protein is likely foreign, it kills the target cell
Because T-cells that bind self-proteins are eliminated during development and cancers look a lot like the body's own cells, T-cells that naturally kill tumors can be rare
At Adaptimmune, we protein engineer and enhance TCRs to target specific cancer proteins that are expressed inside solid tumors
We then genetically engineer these optimized TCRs into a patient's own T-cells, known as autologous cell therapy, to specifically recognize cancer proteins and kill tumor cells
Use of these engineered TCRs is not limited to our autologous platform, though, and these same receptors can be expressed in our allogeneic platform, which is still in preclinical development

Tuba: Showcase your robust pipeline of T-cell therapies.

Dennis:

Our company's mission is to design and deliver cell therapies for cancer and our first marketed product will be a TCR T-cell therapy targeting MAGE-A4, afami-cel, but that is only the beginning for us.
In addition to our Phase 1 SURPASS trial in multiple solid tumor indications with our next-generation SPEAR T-cell targeting MAGE-A4, we plan to initiate a Phase 2 trial with this next-generation product, SURPASS-2, for people with EGJ and esophageal cancers later this year
We also have an ongoing Phase 1 trial against another cancer target, AFP, for people with liver cancer. We reported data from our Phase 1 ADP-A2AFP trial last year at the International Liver Congress (ILC)
At the time of ILC, we reported that nine patients were treated as of the data cutoff, of those
- Four patients were treated with ~5 billion or more transduced cells (three in Cohort 3 and one in the expansion phase): 1 patient with the complete response, 1 with stable disease (SD), and 2 had progressive disease (PD)
- Five patients were previously treated in the first two dose cohorts with doses of 100 million and 1 billion transduced cells, respectively, and all patients had the best responses to SD
We will update data from the Phase 1 ADP-A2AFP trial later this year at the International Liver Cancer Association meeting during an oral presentation on Sep 5
To make our TCR T-cell therapies available to more patients, our preclinical pipeline includes TCRs that recognize more HLA types than our current TCR T-cell therapies
We also have several next-generation enhancements in our preclinical pipeline designed to improve our cell therapies
In addition, we have engineered TCRs that recognize cell surface proteins without the need for HLA, our HLA-independent TCRs or HiTs. HiTs are a very exciting technology that will enable us to go after cancers that are currently targeted by CAR-T and TRuC T-cell therapies
Lastly, we have a tumor-infiltrating lymphocyte or TIL program in collaboration with a leading TIL therapy center (CCIT, Denmark) for next-generation TILs co-expressing IL-7

Beyond our autologous platform, we have a very advanced allogeneic platform or 'off-the-shelf' platform in preclinical development. We can generate T-cells from human induced pluripotent stem cells that can kill cancer target cells in vitro
We can genetically modify these cells to express any of our engineered receptors as well as other enhancements. We can then select and expand banks of these cells to be ready 'on-demand' when an eligible patient needs them.
Our current autologous platform has taught us what it takes to engineer and manufacture cell therapies for cancer and these learnings have informed the development of our allogeneic platform

Tuba: Can you discuss your short-term and long-term goals of the company with our subscribers?

Dennis:

We have a five-year strategic plan called our 2-2-5-2 plan, which we introduced in November of last year
The first aim is to have two commercial products targeting MAGE-A4 on the market in the next five years
We intend the first product to be afami-cel for synovial sarcoma and MRCLS, and we are on track to file the BLA next year
We also plan to initiate a Phase 2 trial with our next-generation T-cells targeting MAGE-A4 in esophageal and esophagogastric junction cancers later this year, which may form the basis of a second approval for a product targeting MAGE-A4, depending on the data
The second aim is to have 2 more autologous TCR T-cell products from our current clinical pipeline on the market in five years. We are continuing to enroll people with multiple solid tumor types in our SURPASS trial, and we aim to identify additional indications to take forward into late-stage
The '5' is for 5 new autologous products in the clinic in five years these could be in additional HLAs, next-generation enhancements, HiTs, or TILs
And finally, to have 2 allogeneic or off-the-shelf products in the clinic in the next five years

About Dennis Williams:

Dennis Williams is the SVP, Late-Stage Development at Adaptimmune since Dec 2019 and is responsible for late-stage pipeline activities, including P-II/III clinical trials through market application submission & approval. Dr. Williams holds a Pharm.D. from the University of Florida and a Bachelor of Science degree in Pharmacy from Temple University.