ASCO 2020: Celyad’s Off the Shelf CAR-T Cell Therapy Shows Promise against Colorectal Cancer

By T. Chakraborty, Ph.D.

The American Cancer Society reports that around 53,200 people would die of colorectal cancer (CRC) in 2020 alone [1]. For patients with metastatic form, the five-year survival rate goes down to 15%, reiterating that a rapid intervention against this cancer is warranted.

Chimeric Antigen Receptor (CAR) T-cell therapy, which involves the use of the patient’s own modified immune cells to combat cancer progression, has been most effective against hematological tumors [2]. The naïve T-cells derived from the patient are genetically altered and combined with their enhanced cytotoxic ability to fight and kill cancer cells [3].

One of the major drawbacks of this therapy is its inability to treat solid tumors. This has led to the rise of allogeneic donor-derived CAR-T cells. In the recently concluded ASCO virtual meeting, Dr. Hans Prenen and colleagues from the University Hospital Antwerp, Belgium, presented their latest research surrounding CYAD-101, an allogeneic CAR-T to treat CRC and gave an update on the Phase I trial.

CYAD 101

CYAD-101, an allogeneic CAR-T cell that expresses the Natural killer group 2D (NKG2D) receptors, was developed by Celyad, a Belgium-based clinical-stage biopharma. NK2GD is expressed on immune cells, and once they bind to the ligands expressed on cancer or antigen-presenting cells, it promotes immune cell activation and proliferation to inhibit cancer growth.

CYAD-101 cells were made using the TCR inhibitory molecule (TIM) peptide-based approach to reduce host graft reaction against cellular infusion. Preclinical data showed that CYAD-101 cells were able to mount an immune response against tumor cells by producing a variety of pro-inflammatory cytokines and chemokines, including Interferon- γ. Moreover, stimulation of the T-cell receptor leads to minimal production of pro-inflammatory factors showing that these CAR-T cells will have reduced graft versus host disease response, which is one of the major concerns for these types of therapies. The preliminary findings of the trial were presented at The Society for Immunotherapy of Cancer annual meeting late last year.

alloSHRINK – Phase I Trail

With the exciting preliminary data, the alloSHRINK trial aimed to evaluate the safety of CYAD-101 CAR-T cell therapy. Fifteen patients with refractory metastatic colorectal cancer were recruited for this study. This is the first clinical trial of its kind using non-gene edited allogeneic CAR-T cell therapy for solid cancer treatment. A bank of 53 billion clinical-grade CYAD-101 cells was produced in two batches composed of mostly CD4+ effector memory T cells, which lacked the expression of immune regulator protein PD-1/Lag3.

CYAD-101 was used in combination with FOLFOX chemotherapy. The patients received CYAD-101 cell infusion on the final day of three successive FOLFOX chemotherapy cycles. Safety analysis showed that only 7 out of 15 patients experienced adverse events that included immune-related events like cytokine release syndrome. CAR-T cell therapy did not show any graft vs. host disease.

From a clinical perspective, two patients showed partial response while nine patients showed stable disease state for three months fueling the potential of this kind of the off the shelf CAR-T cell therapy. It is to be noted that pharmacokinetic studies showed that the serum concentration (Cmax) of CYAD-101 cells was reduced after 2nd and 3rd infusion despite co-treatment with FOLFOX.

This data shows that there is a possibility of host vs. graft response leading to the rapid clearance of the foreign cells from the host body. Dr. Prenen concluded that though the host vs. graft response for CYAD-101 cells has to be studied in greater detail, these types of CAR-T cell therapy gives hope of a quick treatment for previously untreatable cancers [4].

The recent advances in treating solid tumors via CAR therapy have already resulted reached the clinical trial stage. In addition, a clinical trial with CAR-NK cells in patients with metastatic solid cancer is initiated by the Third Affiliated Hospital of Guangzhou Medical University [5]. Further, Juno Therapeutics, in collaboration with Stanford University and Memorial Sloan Kettering Cancer Center, is also conducting a clinical trial to treat patients with recurrent solid tumors using Autologous T Cells Genetically Engineered to Secrete IL-12 [6].

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: ASCO 2020: AstraZeneca and Daiichi Sankyo’s Enhertu Impresses with Benefits in Lung, Stomach and Colorectal Cancer Trials

References

1. https://www.cancer.org/cancer/colon-rectal-cancer/about/key-statistics.html
2. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy
3. https://www.mdpi.com/2072-6694/12/4/842/htm
4. https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.3032
5. https://clinicaltrials.gov/ct2/show/NCT03415100
6. https://clinicaltrials.gov/ct2/show/NCT02498912
7. https://meetinglibrary.asco.org/record/189024/abstract

Author

Tulip Chakraborty