An early-stage immune cell therapy has the potential to induce an immune response against clear cell renal cell carcinoma.
About Renal Cell Carcinoma (RCC)
Renal cell carcinoma (RCC) is the most common type of kidney cancer. Several subtypes of RCC exist, including the most prevalent, clear cell renal cell carcinoma. Around 30% of patients diagnosed with clear cell RCC will progress to metastatic disease, where the cancerous cells spread from a primary site to other parts of the body. If standard systemic first-line treatments fail, patients with progressing clear cell RCC have limited effective options, so continuing to develop new therapies is vital.
What Are CAR T-cells and How Can They Be Used with CRISPR-Cas9 to Treat RCC?
One proposed strategy to treat clear cell RCC involves modifying patients’ immune systems to attack their tumors. Chimeric Antigen Receptor (CAR) T-cells are specialized immune cells called lymphocytes engineered to recognize and bind to specific proteins on cancer cells. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) are tools for genome editing that enable researchers to modify specific genes within cells. Genes can be modified in immune cells (T cells) to help the immune system recognize and eliminate cancerous cells.
CTX130 is an allogeneic CD70-targeted CAR T-cell therapy engineered using CRISPR-Cas9. The term “allogeneic” indicates that the treatment comes from T-cells obtained from healthy donors rather than a patients’ own cells. CTX130 targets the protein CD70, which is present on over 80% of patients with RCC. Researchers at The University of Texas MD Anderson Cancer (MDACC), Houston, conducted a proof-of-concept study to determine if allogeneic CD70-targeted CAR T-cell therapy could improve outcomes for patients with clear cell RCC. Initial results indicated that CD70-targeted CAR T-cell therapy could be effective in patients with clear cell RCC.
Results
The multicenter, international COBALT-RCC trial led by researchers from MDACC investigated the safety and efficacy of CTX130 in sixteen patients with advanced clear cell RCC. Patients were required to be over 18 years of age and have progressed on multiple prior lines of therapy.
First, patients underwent treatment to suppress their own immune cells (lymphodepletion with fludarabine plus cyclophosphamide for three days). Then, CTX130 was administered at one of four dose levels. Six patients received a second infusion, and all other patients received one infusion.
At the median follow-up of 3 years after being treated with CTX130, 63% of patients experienced substantial improvement (objective response rate of 63%). One patient experienced a complete disappearance of their tumor after three months (complete response) and maintained this result after 36 months. The disease control rate among patients receiving CTX130 was 81.3%. The median overall survival for the sixteen patients on this therapy was 20.5 months.
Side effects
No-dose limiting toxicities were observed across all dose levels. Half of the patients experienced cytokine-release syndrome (a hyperactive immune response), but this was minor in all cases and no incidences of severe cytokine-release syndrome were reported. There were no treatment related deaths.
Implications
Initial results were encouraging, CTX130 cells were no longer detectable by day 28 after infusion, suggesting that the therapy either diminished or was eliminated from the body within this timeframe. Using this information, researchers at MDACC made two changes to CTX130 to create CTX131, which they hope will last longer in the body. Researchers have initiated a Phase I/II study to evaluate the safety and effectiveness of CTX131 in adults with relapsed or refractory solid tumors (ClinicalTrials.gov identifier NCT05795595).
References
- “CRISPR: Taking Us to a New Frontier.” Cancer Connect, Cancer Connect, December 2020, https://news.cancerconnect.com/treatment-care/crispr-taking-us-to-a-new-frontier. Accessed 5 July 2024.
- Goodman, Alice. “CRISPR-Edited, Off-the-Shelf CAR T-Cell Therapy Shows Proof of Concept in Renal Cell Carcinoma.” The ASCO Post, HSP News Service, LLC, 25 May 2024, https://ascopost.com/issues/may-25-2024/crispr-edited-off-the-shelf-car-t-cell-therapy-shows-proof-of-concept-in-renal-cell-carcinoma/. Accessed 5 July 2024.
