CTX130 Provides Disease Control and Manageable Safety in Advanced ccRCC

Samer A. Srour, MB ChB, MS

The investigational allogeneic, CRISPR- and Cas9-engineered, CD70-targeted CAR T-cell therapy CTX130 continued to demonstrate an acceptable safety profile and early antitumor activity, including 1 complete response (CR) at 3 years of follow-up, in patients with advanced clear cell renal cell carcinoma (ccRCC), according to updated findings from the phase 1 COBALT-RCC trial (NCT04438083).^1,2

Findings presented at the 2024 AACR Annual Meeting and simultaneously published in Cancer Discovery showed that at the data cutoff of October 9, 2023, 1 patient (6.3%) treated with the first dose level of 3 x 10⁷ CAR T-cells achieved a CR at month 3 and maintained it at 36 months. Notably, the complete responder had a CD70 expression level of 100% at baseline.

Moreover, 75.0% of patients in the overall population (n = 16) achieved stable disease (SD), including 1 patient who maintained SD beyond 12 months. The disease control rate was 81.3%, the median progression-free survival (PFS) was 2.9 months (95% CI, 1.7-6.0), and the median overall survival (OS) was 20.5 months (95% CI, 14.3–not applicable).

“We can clearly say that this is the first CR [achieved with an] allogeneic product that exceeds 3 years in kidney cancer or any other solid tumor,” lead study author Samer A. Srour, MB ChB, MS, explained in a presentation during the meeting. “This study is proof of concept that we can do something [with CD70-directed CAR T-cell therapy] in the solid tumor space, and hopefully we can [go on to] induce durable remissions and cure [patients] based on these results.” Srour is an assistant professor in the Department of Stem Cell Transplantation in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

Approximately 30% of patients with ccRCC develop metastatic disease, and those who progress on standard systemic treatments in the first line, such as checkpoint inhibitor– and VEGF TKI–based combinations, have limited subsequent options.

CD70 is a ligand that interacts with CD27 to control T-cell activation, and it is expressed transiently on activated lymphocytes, natural killer cells, and mature dendritic cells. “In kidney cancer, aberrant CD70 is very highly [expressed in] over 80% of patients. That makes it an ideal target to explore in kidney cancer,” Srour explained during the presentation. “Second, CD70 expression has some suppressive features in the tumor microenvironment, which helps in the aggressiveness of this disease and tumorigenesis. [We hypothesized that] targeting this molecule might help us improve these outcomes.”

CTX130 was designed to target CD70 through disruption of the T-cell receptor alpha constant (TRAC), beta 2 microglobulin (β2M), and CD70 loci using an adeno-associated virus vector to insert an anti-CD70 CAR cassette into the TRAC locus via homology-directed repair.

CTX130 is derived from T cells obtained from healthy donors, which are then selected, edited, and expanded before being cryopreserved for subsequent off-the-shelf use. Preclinical data from an RCC xenograft model were previously reported, indicating potential efficacy of this novel CAR T-cell therapy in ccRCC.

The safety and efficacy of CTX130 in patients with advanced ccRCC were investigated in the open-label, multicenter, international, single-arm COBALT-RCC trial. The study comprised a dose-escalation portion (part A) and a cohort-expansion portion (part B).

Patients with unresectable or metastatic RCC with clear cell differentiation who were 18 years of age or older and weighed at least 42 kg were eligible for enrollment onto the study. Patients were also required to have been previously exposed to both a checkpoint inhibitor and VEGF inhibitor; have a Karnofsky performance status of at least 80%; and have adequate renal, liver, cardiac, and pulmonary organ function.

Key exclusion criteria included prior treatment with anti-CD70 agents; prior exposure to any CAR T cells or any other modified T or natural killer cells; a history of central nervous system, cardiac, or pulmonary conditions; and prior solid organ transplantation or bone marrow transplant.

Once enrolled onto the study, patients underwent lymphodepletion with 30 mg/m2 of fludarabine plus 500 mg/m² of cyclophosphamide for 3 days on days –5, –4, and –3. Infusion of CTX130 began on day +1 at 1 of 4 dose levels: 3 x 10⁷ cells (dose level 1; n = 3), 1 x 10⁸ cells (dose level 2; n = 3), 3 x 10⁸ cells (dose level 3; n = 6), and 9 x 10⁸ cells (dose level 4; n = 4).

“The treatment schema is very much what you see with most CAR T-cell products, with one exception,” Srour noted. “Again, this is an allogeneic product, so you don’t see apheresis and collection. Your patients [can therefore give informed] consent...and within 3 to 5 days, you can start treatment.”

Notably, patients had the option to undergo reinfusion with the CAR T-cell therapy. Srour stated that 6 patients received a second infusion, with all other patients receiving 1 infusion, including the patient who achieved a CR.

In part A of the study, the primary end point was the incidence of adverse effects (AEs) defined as dose-limiting toxicities (DLTs). Key secondary end points included overall response rate (ORR), PFS, and OS.

Across all dose levels, the median age was 63 years (range, 53-77), and 87.5% of patients were male. All patients had metastatic disease and had received prior systemic therapy. Other prior treatments included radiotherapy (68.8%) and surgery (93.8%). The median number of prior lines of systemic therapy was 3 (range, 1-6), and the median time from diagnosis was 4.9 years (range, 0.7-24.0). At the time of screening, 62.5% of patients had intermediate-risk disease per International Metastatic Renal Cell Carcinoma Database Consortium criteria, and 37.5% of patients had high-risk disease. A total of 37.5% of patients had an estimated glomerular filtration rate of less than 60 mL/min/1.73 m².

The initial median CD70 expression level among patients with available baseline and archival tissue was 100% (range, 1%-100%). “We required archive tissue in retrospect to see if [CD70 expression] correlated with response [to CTX130],” Srour said. “Thirteen patients from the [overall population of] 16 had available archived tissue, and the median CD70 expression [among these patients was] 100%, which is what we see in literature.”

Regarding safety, no DLTs were observed across all dose levels. Moreover, there was no incidence of tumor lysis syndrome, hemophagocytic lymphohistiocytosis, immune effector cell–associated neurotoxicity syndrome, graft-vs-host disease, or secondary malignancies. In the overall population, half of patients experienced grade 1/2 cytokine release syndrome (CRS); however, no grade 3 or higher CRS was reported. Grade 1/2 and grade 3 or higher infections were each experienced by 18.8% of patients. Serious AEs related to the investigational agent occurred in 4 patients, all of which were CRS events. Serious AEs of infection unrelated to CTX130 occurred in 3 patients, including 1 patient who experienced grade 5 pneumonia.

Pharmacokinetic analysis showed that most patients had detectable CTX130 levels after infusion, which was then redistributed and declined to a nadir after 2 to 3 days. A subsequent rapid expansion in CTX130 cells was observed with peak concentration achieved on days 7 to 15. This was followed by decline in CTX130 cells, which were no longer detected by day 28.

“We were encouraged by these results, but we thought that maybe we can do better,” Srour explained. "At the same time we were treating our patients with CTX130, there was a parallel study in [patients with] T-cell lymphoma. We saw better responses [in that population, including higher] CR and ORR rates. The CRISPR team went back and performed screening for other edits that we can make to CTX130 to improve outcomes [in patients with ccRCC].”

The CTX131 construct includes 2 knockouts for Regnase-1 and TGFβR2 in addition to TRAC, β2M, and CD70. Preclinical data from xenograft models of RCC have shown superior potency and efficacy with CTX131 vs CTX130. Based on these data, investigators have launched a phase 1/2 study (NCT05795595) assessing the safety and clinical activity of CTX131 in adult patients with relapsed/refractory solid tumors.²

References

1. Srour SA, Tran B, Haanen JB, et al. CTX130 allogeneic CRISPR-Cas9-engineered chimeric antigen receptor (CAR) T cells in patients with advanced clear cell renal cell carcinoma: long-term follow-up and translational data from the phase 1 COBALT-RCC. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT002.
2. Pal SK, Tran B, Haanen JBAG, et al. CD70-targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma. Cancer Discov. Published online April 5, 2024. doi:10.1158/2159-8290.CD-24-0102
3. A safety and efficacy study evaluating CTX131 in adult subjects with relapsed or refractory solid tumors. ClinicalTrials.gov. Updated April 2, 2024. Accessed April 7, 2024. ​​https://classic.clinicaltrials.gov/ct2/show/NCT05795595