Developing More Safe, Precise Next Generation Cell Therapies

In an interview with CGTLive, Marker Therapeutics chief executive officer Peter L. Hoang detailed the company's approach to developing next-generation T-cell therapies with targets in hematological malignancies and solid tumors. Read more below:

Can you tell us about Marker Therapeutics and your approach to next-generation T cell-based immunotherapy?

CAR T-cells use a monospecific approach as in the case of CD19 (or even newer dual-specific CARs); there is limited target recognition for a very heterogenous tumor leading to residual tumor and ultimately tumor relapse. Additionally, an important factor with CAR T-cells or even TIL therapy is the need for lymphodepletion which eliminates endogenous immunity. MultiTAA T-cell therapy approach deals with a heterogenous tumor by targeting multiple different targets beyond just 1-2 targets using nonengineered T cells. We currently have 4-6 targets with the ability to add additional targets, so the specificity of the T cells is quite large leading to improved potency. Moreover, there is no need for lymphodepletion allowing for recruitment of the endogenous immune system leading to epitope spreading and tumor elimination with a more durable response. To summarize, some of the unique benefits of MultiTAA cell therapy is that this technology can target multiple antigens (such as 5 Ag) via native TCR without the need for genetic engineering which leads to a lower cost of producing the product. Also, these T cells are able to initiate epitope spreading by recruiting the endogenous immune system since there is no lymphodepletion required. MultiTAA T cells can recognize both extra/intracellular targets. Ultimately, these cells have been shown to be easy to administer and safe.

How does this approach set Marker apart in the industry among other gene-modified CAR-T and TCR-based therapy developers?

In the current environment where many companies are focused on adding more and more genetic engineering to modify their cells to program them to do what they want, at Marker we are harnessing the T cells' natural ability to kill tumor cells. Our goal is to identify and expand the T cells that we believe will be doing a majority of the killing using a library of peptides that span various antigens to isolate the T cells of interest. As a result of isolating the specific T cells to kill the tumor cells, the safety profile of this technology is very manageable without any evidence of cytokine release syndrome or neurotoxicity. As a result, multiTAA T cells are administered as a 10-minute infusion at the clinic in an outpatient setting without the need for hospitalization or ICU stay.

I do want to highlight a few unique features that the safety profile and administration affords us. First, the cells can be administered easily in a community setting since it can be done in outpatient so it is more accessible to patients and the patient does not require lymphodepletion. Secondly, because of the tolerable safety profile, it can be administered in patients in remission but may have high risk of disease recurrence such as in the adjuvant setting which is not typical of other cellular therapies and broadens the opportunities for administration of this therapy compared to others. Lastly, it also allows for combinations to be done more easily since you wouldn’t want to consider combining 2 toxic regimens together. A good example of this is a pancreatic cancer study where we can easily combine with frontline combination chemotherapy such as FOLFIRINOX which can be quite toxic.

Why did Marker decide to focus on hematological malignancies and solid tumor indications?

The ability to work with Baylor allows us to determine which studies we would like to move forward based on a number of different factors including phase 1 data in combination with high unmet medical need in both hematological malignancies as well as solid tumors. Acute myeloid leukemia (AML) fit these 2 characteristics in the sense that the phase 1 data looked promising and AML has a high unmet medical need particularly in the post-transplant setting. Additional hematological malignancies such as lymphoma and solid tumor indications such as pancreatic cancer also fits this bill and provides promising phase 1 data that we would like to explore further.

How exactly does the MultiTAA technology enable Marker to develop more precise and safer therapies?

The administration and safety profile is quite simple. MultiTAA T cells are administered as a 10-minute infusion at the clinic in an outpatient setting without the need for hospitalization or ICU stay. The dose is typically 20 million/m² squared with 3 infusions over 2-4 week intervals, but we have moved to a flat dosing for the phase 2 AML study. The safety profile has been shown in over 150 patients treated. There have been no dose-limiting toxicities, cytokine release syndrome, or neurotoxicity observed. MultiTAA T cells are easy to administer and well tolerated such that it can be used in both the adjuvant and active disease setting.

Now, if you look at other cellular therapies such as CAR T cell technology which requires administration in the ICU setting for extensive monitoring for cytokine release syndrome and neurotoxicity or TIL therapy which also requires lymphodepletion along with cytokine support, multiTAA T cell therapy is much easier to administer and safer in comparison.

What updates can you provide on the phase 2 AML study?

Cohorts 4 and 5 using the new manufacturing process with the higher doses will be expected to finish around mid-year 2022. In addition, we will have an update for the active disease patients treated with the previous manufacturing process around mid-year as well.

Please tell us more about Marker's pipeline activity.

In Marker's pipeline, there is an off the shelf program with MT-401-OTS. An off the shelf program expands our treatment capabilities. We started with 1 patient-specific MT-401 product that we are exploring in our phase 2 AML study where each product is tailored to the patient. We then have extended into the off the shelf product which will allow administration of that product to greater than 100 patients and the ability to expand beyond AML to other hematological malignancies and solid tumor indications.

Additionally, there is other ongoing preclinical work exploring up to 12 additional antigens as well as combinations with other agents such as hypomethylating agents and peptide vaccines.

Marker recently announced an improved T cell manufacturing process. Can you elaborate on that?

We have invested considerable effort into improving and industrializing the manufacturing process.

While we were very impressed with the clinical results that BCM was able to generate in its phase 1 trials, we recognized that it would be necessary to make the process simpler, more robust, more repeatable and scalable in order to commercialize the therapy. We took the following steps to do so:

1. Simplification of process from ~3000 to <20 technician interactions per SOP (reduces potential for manufacturing failure, improves consistency)
2. Reduced manufacturing time (minimize time for progression, better throughput through same infrastructure)
3. Aimed to maintain product efficacy but actually saw phenotypic and biologic improvements in process

As such, Marker's GMP:

1. Improves capacity
2. Allows for better control of process and manufacturing
3. Is less expensive than a CMO
4. GMP facility is built in a modular fashion to reduce cost and improve scalability
5. Simple tech transfer given that the process was developed at Baylor

What else can we expect to hear from Marker though the end of 2022?

Marker has a lot of different activities going on from now until end of 2022 including AML phase 2 result updates, the start of lymphoma study and submission of pancreatic cancer IND.

Transcript has been edited for clarity.