First-in-Class Allogeneic CAR T Cell Shows Antitumor Activity in mCRC

Frederic Lehmann, MD

Frederic Lehmann, MD

An NKG2D-based chimeric antigen receptor (CAR) T-cell therapy, CYAD-101, induced promising responses in the phase I alloSHRINK trial, presented at the Society for the Immunotherapy of Cancer (SITC) 34^thAnnual Meeting. This novel, off-the-shelf allogeneic  CAR T-cell therapy was evaluated in the dose-escalation trial in association with FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) as preconditioning chemotherapy to help induce responses in patients with metastatic colorectal cancer (mCRC).

Two out of 12 patients achieved a confirmed partial response (PR) according to RECIST 1.1 criteria, while 5 patients achieved stable disease for a duration of at least 3 months. Investigators also noted a tumor burden decrease in 6 of the 12 patients enrolled in the study.

The treatment was generally well-tolerated with no dose-limiting toxicities. Half of the patients (6/12) reported at least 1 treatment-related adverse event (TRAE), but all TRAEs were grade 2 or below. Only 1 patient reported cytokine release syndrome, and no patients discontinued due to toxicity.

The alloSHRINK trial is an open-label, phase I dose-escalation study to establish the safety and clinical activity of CYAD-101. The agent is administered in 3 consecutive doses every 2 weeks, and FOLFOX is administered concurrently.

In an interview withTargeted Oncology, Frédéric Lehmann, MD, vice president of Clinical Development & Medical Affairs at Celyad, discussed the results for the alloSHRINK trial that were presented at the SITC 34^thAnnual Meeting. The allogenic CAR T-cell therapy, CYAD-101, in association with FOLFOX chemotherapy showed promising antitumor activity in patients with refractory mCRC.

TARGETED ONCOLOGY: Could you provide some background to the CYAD-101 CAR T cell product?

Lehmann:CYAD-101 is 1 of our allogenic CAR T cell therapies. CYAD-101 is on the specific antigen receptor called NKG2D receptor. NKG2D is quite interesting and is expressed on NK cells, which is important in the physiology of the control of infectious disease and tackling cancer cells. The NKG2D receptor is recognizing different ligands MICA, MICB,  and BP126. It is quite important because as you know, in the context of oncology, a clonal selection is when you are using 1 targeted therapy. 

In that context, tackling different antigens on the surface of 1 cell, it’s important. However, in the context of the allogenic CAR T, CYAD-101, we are also involving 1 construct that has a non-gene edits technology, called the T cell receptor (TCR) Inhibitory Molecular (TIM). This is competing with the [signaling] of the TCR, which is, therefore, aggregating the expression of the TCR at the surface of the cells. We do believe it will impact [disease] by decreasing the function of the TCR and therefore aggregating any graft-versus-host disease (GvHD) with the use of an allogenic CAR T product.

TARGETED ONCOLOGY: What is the rationale for combining CYAD-101 with FOLFOX chemotherapy in mCRC?

Lehmann:There are different rationales. The first is the most critical, which is we want to combine this off-the-shelf allogenic CAR T with chemotherapy in order to induce a lymphocyte depletion status in order to avoid any host-versus-graft (HvG) reactions. As you know, if we inject allogenic T cells into the patients, those cells would be rapidly rejected by the system of the patients. Therefore, 1 of the options is to induce a transient lymphodepletion, which is what we induce with the FOLFOX chemotherapy. In that context, it is critical that the design of this study be in mCRC patients who have already received chemotherapy-based oxaliplatin- or irinotecan-based chemotherapy.

The global rationale of combining the allogenic CAR T CYAD-101 with FOLFOX chemotherapy is to use the FOLFOX chemotherapy as a preconditioning therapy. Knowing the context of the allogenic therapy, if you inject the CYAD-101 cells, they will be rapidly rejected by the system of the patient. By proposing to the patients to use a preconditioning of chemotherapy like FOLFOX, we induce a long-lasting lymphodepletions, which will therefore control and reduce the risk of HvG reactions. Moreover, the FOLFOX chemotherapy is for the stress-induced ligands of the cells. We will induce a huge expression of those ligands, which are the target of the NKG2D.

TARGETED ONCOLOGY: How was the alloSHRINK trial designed?

Lehmann:The alloSHRINK study is a phase I dose-escalation study evaluating the CYAD-101 allogenic CAR T with concurrent FOLFOX chemotherapy. The FOLFOX is given as a preconditioning chemotherapy, and it has no intent to have an impact on the disease because the patient population is unresectable, progressing mCRC patients who have progressed under metastatic line of oxaliplatin or irinotecan.

It is a dose-escalation study where we evaluated 3 dose levels of the CYAD-101. The first dose level was 100 million cells [per infusion], level 2 was 300 cells [per infusion], and the third level included 1 billion cells per infusion. Each of the patients are receiving infusions of the allogenic CAR T cells at day 3 of a classical cycle of chemotherapy with the standard of care of the FOLFOX, which is administered every 2 weeks. The patients receive 3 infusions of the allogenic CAR T and at least 3 consecutive cycles of FOLFOX.

TARGETED ONCOLOGY: What were the results that were presented?

Lehmann:As of to-date, 12 patients have been enrolled in that study of 15 patients. It is a classical 3:3:3, so 3 patients have been dosed at level 1, 3 patients at dose level 2, and as of today, 6 of the 9 patients have been enrolled at dose level 3. Global backgrounds of the patients are classical for a phase I study in the mCRC population. The mean age was 55 years old, the ECOG performance status was 0 or 1, and the median metastatic treatment line is between 1 to 6 with a mean of 3. The tumor is also quite interesting because all of those tumors are microsatellite stable, two-thirds areKRAS-mutated, and 20% areBRAF-mutated.

The primary endpoint of this study is to define the recommended phase II dose based on documentation of dose-limiting toxicities, including the GvHD. Key secondary endpoints are the cell kinetics, such as the engraftment of those cells, and even though it is a phase I dose-escalation study, we are looking at the clinical activity, such as objective response rate and duration of dose response rate.

In terms of safety, the data are quite encouraging. The combination of the CYAD-101 with FOLFOX does not generate any major safety concerns. It is very well tolerated, and no dose-limiting toxicities have been documented. No GvHD on the clinical point of view or the biologic point of view have been documented. There were no TRAEs above grade 2. No patient stopped treatment due to TRAEs. Interestingly, only 1 patient presented with cytokine release syndrome.

The secondary key endpoint is the use engraftment of those CYAD-101 allogenic CAR T cells in the context of FOLFOX lymphodepletions. The chemotherapy data were quite interesting because they are an engraftment of those cells, so at each dose level we are able to detect the CYAD-101 in the peripheral blood, even at the third injections. Interestingly, the dose is in the same range of the dose that was obtained with the sister study, the SHRINK study, where the autologous product is administered in association with the FOLFOX chemotherapy as well.

We know the transient lymphodepletion inducing by the FOLFOX chemotherapy perfectly controlled the HvG reaction in order to [control] the engraftment of those cells.

TARGETED ONCOLOGY: Were there any other significant findings to note on this combination?

Lehmann:What was maybe more intriguing and promising of the clinical results is the clinical impact on the disease. Out of those 12 patients, 2 objective responses have been obtained which were 2 PRs, including 1 PR has been lasting for more than 6 months. I have to remind you that this patient population that is refractory to FOLFOX or irinotecan chemotherapy usually have a limited median survival of a few months, and usually the standard of care for such populations is regorafenib (Stivarga) or TAS-102 (trifluridine/tipiracil; Lonsurf), where 1 to 5 persons have objective response, which is mainly PR and no complete response.

In our context, 2 PRs out of 12 sounds very promising. Moreover, we do induce a disease control in 7 of the patients with long stable disease. Five patients have stable disease of 3 months, and some stable disease still ongoing for more than 4 months. Globally, 6 of the 12 patients are presenting a tumor decrease, so some of the stable diseases are presenting tumor decrease, but unfortunately these patients are not fit to have a PR according to the RECIST 1.1 criteria.

Reference:

Celyad Highlights Safety and Clinical Activity of CYAD-101, a First-In-Class, Non-Gene Edited Allogeneic CAR-T Therapy for mCRC, from SITC 34th Annual Meeting. Business wire web site. https://bwnews.pr/2LgGHBa. Published November 11, 2019. Accessed December 3, 2019.