Is Off-the-Shelf Immunotherapy the Way Forward?

Chimeric antigen receptors (CARs) are engineered receptors that can be expressed on the T cell surface, that enhance the T cell’s ability to recognize and destroy cancer cells. This approach is known as CAR T therapy, which has shown promise in several types of cancer. Current CAR T approaches utilize the patients’ own immune cells.

CAR T therapy does present some challenges and limitations, and the field is always searching for new ways to improve.

To learn about different approaches, we spoke to André Choulika, Chairman & CEO of Cellectis. Cellectis is developing immunotherapies using a different CAR T therapy approach, whereby cells are derived from healthy donors. 

Michele Wilson: What are the biggest unmet medical needs that Cellectis is currently focusing on, and how did that come about?

André Choulika (AC): While it’s clear that gene editing is coming to the forefront of cancer treatment in today’s society with the FDA approval of Novartis’ Kymriah and Kite’s Yescarta, both of these use the autologous approach, which focuses on using a patient’s own T-cells to create the treatment. This has serious constraints, including high pricing and limited market access, highlighting the need to personalize medicine on a larger scale.

In an attempt to fill this need, Cellectis is developing “off-the-shelf,” or allogeneic, CAR T-cell products, which are made from the cells of healthy donors. In this way, these products can be manufactured on an industrial scale, getting to patients faster and in a more cost-effective way since this therapy was not developed using each individual’s cells. Think of it as grabbing a cure for cancer right out of the freezer whenever a patient needs it. This ultimately represents the next transformative step in medicine.

Furthermore, allogeneic products can be available for all patients globally, including those who are unable to produce autologous CARs and patients in countries where the technology is not yet available. There are also lower logistical complexities and associated costs, as allogeneic products can be shipped within a few days worldwide and have the potential to reduce the final cost. Re-dosing is even possible with this approach, which contributes to a patient’s overall survival.

Cellectis has two wholly-controlled products in the clinic right now: UCART123 for acute myeloid leukemia and UCART22 for acute lymphoblastic leukemia. These are the first gene-edited off-the-shelf CAR T-cell product candidates to be developed in the U.S. Additionally, the Cellectis team developed UCART19, exclusively licensed to Servier and under joint development agreement between Servier and Allogene. The promise of off-the-shelf universal CAR T-cell therapies is enormous for people living with certain blood cancers.

MW: Why is the ability to selectively deplete CAR T-cells important to have in a clinical setting?

AC: CAR T-cells continue to multiply inside of the patient as soon as the cells spot their cancer target in the blood. As the CAR T-cells strike the tumors, they release cytokines, which cause inflammation. When this happens too quickly, it can cause a life-threatening response called a cytokine storm. If the patient has an extreme cytokine storm, having a way to selectively deplete CAR T-cells would be a lifesaver.

Video credit: Cellectis

MW: Can you tell us about TALEN® gene editing? What makes it unique?

AC: TALEN® is Cellectis’ flagship proprietary gene editing technology. TALEN® products are genome engineering enzymes that can introduce changes into the DNA code with high specificity and activity, effectively generating nucleases that bind and cleave DNA sequences only at pre-selected sites. Cells can be engineered with optimized features for cancer therapies, drug discovery, gene function studies, industrial biotechnology and more.

We use TALEN® because of the precision, the efficacy and the safety that it allows. You can place the cut within 6 base pairs of any target in the genome, making TALEN® very precise and highly potent. When combining this precision with the technology’s specificity and over 95% efficiency, TALEN® has been successfully used in the clinic to solve key challenges with allogeneic CAR T including protection from graft versus host disease, mitigation of rejection and enhanced safety via a suicide switch.

MW: What is the CubiCAR, and how do you see it improving the safety of CAR T-cell therapies?

AC: Cellectis developed the CubiCAR architecture, an all-in-one CAR architecture with an embedded multi-functional tag for the purification, detection and elimination of CAR T-cells. This versatility has the potential to streamline the manufacturing of CAR T-cells to allow their tracking and efficiently eliminate CAR T-cells in clinical settings. This has the potential to improve the safety of CAR T-cell immunotherapies for a broad range of patients who have cancer.

MW: What techniques and research models have you used to help validate UCARTS?

AC: We extensively test our UCART therapies in a number of research models in order to demonstrate that they can specifically and efficiently eliminate tumor cells. These tests are performed with sample tumor cells in culture or in mouse models. The purpose of this is to ensure that the technology is targeting the correct cells and showing effective results. Once we’ve analyzed these data and demonstrated successful responses, we work with appropriate regulatory agencies and medical centers to set up clinical trial sites. From here, we work with physicians and patients on dose escalation studies and other trials to see how we can best optimize the treatment to help the human body. The next phases are expansion phase trials once the dose has been determined and then the registration trial in order to get these products commercialized in a few years.

André Choulika was speaking to Michele Wilson, Science Writer for Technology Networks