Engineering Innovative CAR T-Cell Therapy Candidates for Cancer

Celyad Oncology is a clinical-stage biotechnology company centered on the development of chimeric antigen receptor (CAR) T-cell therapies for the treatment of cancer. This approach involves engineering patient or donor T cells to display a CAR that targets the immune cells to cancer cells via antigen–receptor binding.

Technology Networks recently had the pleasure of speaking with Celyad Oncology’s CEO Filippo Petti. In this interview, Petti discusses key immunotherapy advances, highlights the two main CAR T-cell therapy approaches and elaborates on the company’s “off-the-shelf” CAR T cells.

Laura Lansdowne (LL): How have advances in immunotherapy influenced the landscape of cancer drug discovery in recent years? 

Filippo Petti (FP): The immunotherapy industry is an ever-evolving landscape, with interest in checkpoint inhibitors, chimeric antigen receptor (CAR) T cells and bispecific antibodies exploding in the past few years. This era of cancer therapy has allowed us to treat new and difficult cancer indications (including solid tumors), harness the immune system in a novel way and target new pathways. Not only are immunotherapies showing promise as stand-alone treatments, they have also shown great potential to be administered in combination with other types of treatment, including targeted therapies, for greater benefit to patients.

At Celyad Oncology, we are specifically arming T cells to target and destroy cancer cells using CAR T-cell therapies. T cells can be genetically engineered to express a receptor designed to aid in the recognition of the cancer cell by binding a specific antigen or ligand(s) present on the surface of the cancer cell. While CAR T cells are becoming a better explored therapy in the industry, we are working to pioneer a different approach to treat cancers with the most unmet need.

LL: Can you elaborate on the potential of CAR T-cell therapy more specifically and can you touch on the two main approaches in the field of CAR T?

FP: There are two main approaches in the CAR T field – autologous and allogeneic therapies. 

Autologous CAR T-cell therapy is developed by collecting a patient’s own cells at the time of need, shipping the immune cells to a manufacturing facility, genetically engineering the T cells so they are better suited for fighting that person's cancer and shipping the enhanced cell therapy back to the patient for administration.

Allogeneic CAR T-cell therapy is created from healthy donor T cells that are shipped to the manufacturing facility to be genetically engineered well in advance of being needed by a cancer patient. However, the cells are also engineered with an additional technology used to limit the potential for a graft versus host reaction when administered to patients different from the donor.

CAR T is a promising therapy to treat cancer, but it has yet to reach its full potential. Researchers still struggle to effectively target a broad range of tumor types and to scale production for common cancers that affect large numbers of patients.

To overcome this challenge, we use a CAR based on the natural killer cell receptor, called NKG2D, to target stress ligands on tumors. Up to 80% of tumors express NKG2D ligands, including both hematologic and solid tumors, which gives CAR T cells engineered with the NKG2D receptor broad potential to treat multiple types of cancer. This year, we released industry leading clinical data showing the effectiveness of an allogeneic CAR T therapy in solid tumors for the first time. Our data showed two (of 15) patients achieved a confirmed partial response and nine patients had stable disease in refractory colorectal cancer. The allogeneic approach also allows us to create large batches of engineered cells that can help large patient populations.

LL: What is Celyad’s “All-in-One Vector Approach”? How is it used to generate off-the-shelf CAR T cells and what are the key advantages to using this approach?

FP: We are using non-gene edited technologies, including short-hairpin RNA (shRNA), to create T cells that can be used as an “off-the-shelf” allogeneic therapy for cancer patients in an industry where most people are relying on gene editing techniques like CRISPR. We have shown that the efficiency of RNA interference using shRNA technology in reducing gene expression is comparable to gene editing but uses a simpler approach. For instance, the shRNA can be incorporated into a single vector alongside our receptor, thus reducing the amount of genetic engineering steps used in production. In addition, the current single vector strategy we employ allows for positive selection of CAR T cells we produce as compared to gene editing approaches that only rely on a negative selection process, which is more challenging and less efficient.

Using shRNA could also greatly increase the potential to engineer CAR T cells with desired features that enhance anti-tumor activity. Recent data show multiple genes can be silenced using shRNA when producing CAR T cells. Overall, shRNA technology offers the potential to improve effectiveness, production and costs of off-the-shelf CAR T therapies using a “plug and play” approach. 

LL: Could you tell us more about some of the next-generation allogeneic and autologous CAR T candidates you are developing and the indications they are designed to treat?

FP: We have several promising candidates in clinical development with major upcoming milestones.

We recently received clearance by the US Food and Drug Administration (FDA) to start the Phase 1 IMMUNICY trial using our new shRNA-based allogeneic CAR T candidate CYAD-211 for the treatment of relapsed/refractory multiple myeloma by year end 2020. This is a huge milestone as it’s a first-in-class shRNA-based CAR T candidate for this patient population.

For CYAD-101, our TIM-based (T cell receptor inhibitory molecule) allogeneic NKG2D candidate, we expect to begin enrollment in an expansion cohort of our Phase 1 alloSHRINK study in Q4 2020, for the treatment of refractory patients with advanced metastatic colorectal cancer with microsatellite stable (MSS) disease. In addition, we recently announced a clinical collaboration with MSD, a subsidiary of Merck & Co., to evaluate CYAD-101 with the anti-PD-1 therapy KEYTRUDA® (pembrolizumab) for the treatment of refractory mCRC in the KEYNOTE-B79 trial which is expected to begin during H1 2021.

We’ll also be reporting preliminary data for our dose-escalation Phase 1 CYCLE-1 trial evaluating CYAD-02 and our dose-expansion Phase 1 THINK trial evaluating CYAD-01 in relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome by year-end 2020. CYAD-02 is our next-generation autologous NKG2D-based CAR T that incorporates shRNA technology targeting genes that could help increase the expansion, engraftment and persistence of this therapy in patients.

Filippo Petti was speaking with Laura Elizabeth Lansdowne, Senior Science Writer for Technology Networks.