Q&A: Current affairs for CAR T

Celyad details current obstacles faced by CAR T approaches, and its own efforts to address them

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Chimeric antigen receptor (CAR)-T cell therapy is one of several efforts to retrain the immune system to better target cancer. This tactic involves taking T cells from a patient, engineering them to attack certain cancer targets by adding a receptor that binds to a given protein on the surface of cancer cells, and then infusing them back into the patient. Many companies have their own approaches for trying to harness this therapy, and among them is Celyad SA. Filippo Petti, Celyad’s CEO, sat down with DDNews to explain more about the company’s CAR-T technology and the roadblocks within this field.
DDNews: How is Celyad taking a new approach to CAR-T therapies?
Filippo Petti: To date, the FDA and EMA have approved only two autologous CAR-T therapies, both of which aim to treat relapsed/refractory B-cell malignancies by targeting the blood cancer-specific antigen CD19 which is found on the surface of B-cells. However, since the expression of CD19 cell surface protein is limited to B-cell malignancies, the applicability of these novel personalized treatments is restrictive in nature. In general, most of the CAR-T field is focused on a single target approach leading to the design of a novel CAR-Ts focused on a specific target/protein and disease indication.
Celyad’s differentiated approach aims to address this shortfall. Both of Celyad’s current clinical CAR-Ts are centered on an activating receptor known as NKG2D, which is primarily found in natural killer (NK) cells. Importantly, NKG2D binds eight different major histocompatibility complex class I-related (MHC class 1) ligands, including MICA, MICB and the ULBP proteins 1–6, which are induced in response to stress such as the induction of the DNA damage pathway.
Both clinical candidates exploit the broad target specificity of the NKG2D receptor in a T cell format—the NKG2D receptor is fused with the intracellular domain of the CD3ζ chain of the T cell receptor complex and expressed within a T cell, resulting in CAR-Ts that are able to activate its killer functions following engagement of the NKG2D receptor with one of its eight target stress ligands. Importantly, the signals through both the CD3ζ chain (primary) as well as the adaptor protein DAP10 (secondary), which is endogenously expressed in T cells and naturally associates with the NKG2D-CD3ζ receptor fusion protein at the cell surface.
The company is evaluating both an autologous approach (using the cells of the patient) and non-gene editing allogeneic approach (based on cells from healthy donors) with its NKG2D-based CAR-Ts. 
In addition, Celyad is the only company conducting clinical trials evaluating its CAR-T candidates without treating patients with preconditioning chemotherapy, or lymphodepletion. In traditional CAR-T clinical development, patients typically receive the CAR-T treatment following preconditioning chemotherapy. The preconditioning chemotherapy helps to deplete endogenous lymphocytes, thus reducing immunosuppressive cells while providing an opportunity for the injected CAR-T cells to expand and engraft. Importantly, the preconditioning chemotherapy also has an impact on the underlying disease.
As such, the data reported to date for Celyad’s CAR-T program strongly suggest that the clinical activity seen within the program is directly associated to the NKG2D CAR-T therapy, with no effect attributed to any chemotherapeutic agent.
DDNews: What makes CYAD-01 a near-universal CAR-T candidate?
Petti: CYAD-01 is our first NKG2D CAR-T. Our lead immune-oncology candidate is being evaluated in patients with both advanced hematological malignancies and solid tumors. As NKG2D ligands are highly expressed across many different tumor types, NKG2D-based CAR-T cells could potentially address up to 80 percent of all cancers, thus making CYAD-01 a near-universal CAR-T.
DDNews: Which ligands does CYAD-01 target, and what are some of the cancers that feature those ligands?
Petti: NKG2D binds to eight known proteins which are present on cells that are stressed. In its normal situation, NK cells, part of the innate immune system, use NKG2D to scan the body for the presence of these stress signals on cells which could be indicative of a virus infection or cancer. In this way, infected cells can be rapidly identified and destroyed thereby halting the spread of infection or cancer. Flagging of cells with these ‘stress ligands’ is very powerful thus NKG2D ligands are absent or expressed at low levels in normal, healthy cells.
Because tumors are stressed cells, mainly due to the damage of the cell’s genome requiring constant repair of their defective genes, stress ligands are present across many different cancer indications, including: Acute myeloid leukemia, bladder, chronic myeloid leukemia, colorectal, lymphoma, multiple myeloma, non-small cell lung cancer, ovarian, pancreatic and triple negative breast.
DDNews: In brief, can you describe the benefits and what’s unique about allogeneic therapies as cancer treatments?
Petti: With autologous therapies, there is a time lag between the isolation of the patient’s immune cells, the production of the CAR-T therapy and the actual delivery of the therapeutic T cells back to the patient. This time is associated with the manufacturing of the therapy and with performing quality control of the CAR-T cell product. 
Alternatively, allogeneic CAR-T cells are produced from immune cells of a heathy donors, stored and ready for use when the patient requires treatment. There is no delay in treatment similar to that associated with an autologous approach regarding production of the personalized immune cells. As such, the paradigm with allogeneic cell therapy represents a strong advantage, especially in the treatment of aggressive indications, as the patient’s disease will continue to progress while they await the production of the personalized CAR-T therapy. There is also risk associated with the potential for the isolation of the patient’s immune cells as starting material to be poor quality, i.e. there may be a low number of immune cells or the healthiness of the patient’s immune cells may be poor as well. As such, these factors may impact the patient’s eligibility to receive the CAR-T treatment.
One major drawback of allogeneic CAR-T therapies is having to avoid graft-versus-host disease (GvHD). GvHD results when donor T cells infused into the patient attack the patient’s healthy tissues or cells, as they recognize the host cells as “non-self.” One way to prevent this side effect is to eliminate the T cell receptor (TCR) complex on CAR-T cells, as the TCR is associated with recognition. Many CAR-T companies are using gene-editing technologies to knock-out a specific gene coding for a protein of the TCR.
However, Celyad is focused on an alternative strategy to generate allogeneic CAR-T cells using non-gene edited techniques. Our aim is to disrupt the expression of the TCR in the absence of genome editing, thereby circumventing possible safety concerns with the approach. We are currently evaluating two non-gene edited allogeneic technologies.
The first involves the expression of our TIM (T-cell inhibitory molecule) peptide which acts as a competitive inhibitor to the CD3ζ component of the TCR, which then dampens the TCR’s ability to signal and potentially lower the risk of GvHD. The second approach focuses on the RNA interference through the expression of a short hairpin RNA (shRNA) to knock down gene expression of the CD3ζ component of the TCR. In both in-vitro and in-vivo preclinical models, the shRNA approach shows similar knockdown of the TCR complex when compared to a gene-edited approach to knockdown the TCR and prevent GvHD. However, a very important differentiation point between the shRNA and gene-editing approach is that the T cells generated with shRNA show a statistical difference in persistence when compared to the gene-edited approach.
DDNews: Why is scaling up production of CAR-T therapies an issue within this treatment space?
Petti: Currently marketed CAR-T therapies carry a very high price tag in part because of the manufacturing processes associated with personalized, autologous therapies. To ensure manufacturing does not slow down clinical development or commercialization of our therapies, Celyad established a top-tier manufacturing facility across from our headquarters in Mont-Saint-Guibert, Belgium. Focusing on process development of our lead asset, CYAD-01, Celyad has gained substantial cell yields compared to academic methods that were first used to produce the CYAD-01 CAR-Ts. The Mont-Saint-Guibert facility offers Good Manufacturing Practice, Quality Control and Quality Assurance departments with more than a decade worth of experience in the production of cell therapies. Importantly, the facility currently supplies all clinical development programs through cryopreserved products to both U.S. and EU clinical sites, and is equipped to support over 1,000 patients annually.
DDNews: Next to CYAD-01, what are some of the other promising programs Celyad is focused on advancing?
Petti: Our second clinical candidate, CYAD-101, is an allogeneic NKG2D-based CAR-T. It utilizes the TIM technology to disrupt TCR signaling. In parallel, we continue to work on our allogeneic shRNA platform and plan to validate the technology through clinical trials with well-understood CAR-T targets BCMA and CD19, through our CYAD-211 and CYAD-221 programs, respectively. Eventually, we plan to nominate a dual-specific, shRNA-based allogeneic candidate, CYAD-231, expressing the NKG2D receptor along with an undisclosed receptor. Lastly, the company is also progressing with next-generation autologous NKG2D CAR-T therapies as well.

Before becoming CEO, Filippo Petti previously served as Celyad’s chief financial officer after having held roles in healthcare investment banking at Wells Fargo Securities and William Blair & Co. Prior to that, Petti worked at William Blair & Co. and Wedbush Securities, studying equity research, and at OSI Pharmaceuticals Inc. as a research scientist in drug discovery and translational research.

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