Dr Srour on the Ongoing Investigation of CAR T-Cell Therapy in Advanced RCC

Samer A. Srour, MB ChB, MS, assistant professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the investigation of the allogeneic CAR T-cell therapy CTX131 in patients with advanced clear cell renal cell carcinoma (ccRCC).

Updated findings from the phase 1 COBALT-RCC trial

 (NCT04438083), which evaluated CTX130 in patients with advanced ccRCC, were shared at the 

. Notably, CTX130 is an allogeneic CAR T-cell therapy similiar to other commercially available CAR T-cell therapies approved for patients with hematologic malignancies. These outcomes left investigators feeling optimistic, yet as researchers, Srour states that he and colleagues perpetually seek avenues for improvement, posing a critical question: Could outcomes be enhanced beyond current achievements, such as bolstering disease control rates above 80%? Consequently, investigators embarked on a quest to identify potential genetic modifications for CAR T-cell therapy that could elevate efficacy levels. Although patient enrollment and treatment with CTX130 were ongoing, parallel efforts were underway to refine the therapy, Srour reports.

Through experimentation, investigators identified 2 promising modifications that showed considerable promise in enhancing the potency and longevity of CAR T-cells, thereby amplifying their persistence within the body, Srour expands. Additionally, targeting the TGFβreceptor proved instrumental in overcoming the suppressive nature of the tumor microenvironment, according to Srour. By eliminating this barrier, CAR T-cells were empowered to better infiltrate and combat tumors, Srour says. These advancements culminated in the development of CTX131, the next iteration of CDX130, which embodies these critical genetic enhancements, he elucidates.

Presently, the investigation of CTX131 is underway at The University of Texas MD Anderson Cancer Center and other institutions, Srour continues. Although still in its early stages, investigators have commenced treatment on a select cohort of patients. Investigators anticipate accumulating valuable insights and data that will further elucidate the potential of CTX131, Srour concludes.

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Samer A. Srour, MB ChB, MS, discusses the investigation of the allogeneic CAR T-cell therapy CTX131 in advanced clear cell renal cell carcinoma.

Dr Srour on Toxicities Associated With CAR T-Cell Therapy in RCC and Other Solid Tumors

Samer A. Srour, MB ChB, MS, assistant professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses difficulties associated with the utility of the allogeneic CAR T-cell therapy CTX130 in patients with advanced clear cell renal cell carcinoma, as well as in other solid tumor patient populations.

was evaluated in the phase 1 COBALT-RCC trial

 (NCT04438083), findings from which were presented at the 

. When considering commercially available CAR T-cell products for the management of hematologic malignancies, the foremost challenges associated with CAR T-cell therapy lie in its unique toxicities, Srour begins. These include cytokine release syndrome (CRS), neurotoxicity such as immune effector cell–associated neurotoxicity syndrome (ICANS), and the rare but serious complication known as hemophagocytic lymphohistiocytosis, (HLH), he explains. In the context of CAR T-cell therapy for solid tumors, particular attention is paid to these 3 distinctive toxicities, Srour adds.

The safety profile of CTX130 is promising, according to Srour. Notably, in COBALT-RCC, CRS events were limited to grades 1 and 2, aligning with observations from studies of similar CAR T-cell products, he expands. Encouragingly, no instances of ICANS or HLH were observed, marking a significant milestone in safety, Srour states. Moreover, infections, a concern associated with CAR T-cell therapies for hematologic malignancies, did not manifest as grade 3 or higher events attributable to CTX130, Srour notes. This comprehensive safety assessment underscores the favorable safety profile of CTX130 in the context of these high-risk patients, Srour reports.

The absence of severe CRS and ICANS, coupled with the lack of HLH occurrences, highlights the potential of CTX130 to mitigate the toxicities commonly associated with CAR T-cell therapy, he continues. The low incidence of grade 3 or higher infections further reinforces the favorable safety profile of CTX130 in this patient population, Srour says. These findings offer promising implications for the broader application of CTX130 in hematologic malignancies, indicating its potential to address critical safety concerns and deliver therapeutic benefits to patients, he concludes.

Samer A. Srour, MB ChB, MS, discusses toxicities associated with CTX130 in advanced clear cell renal cell carcinoma.

Samer A. Srour, MB ChB, MS, discusses the utility of the CAR T-cell therapy CTX130 and unmet needs in advanced clear cell renal cell carcinoma.

Dr Srour on the Utility of CTX130 in RCC

Samer A. Srour, MB ChB, MS, assistant professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the utility of the allogeneic CAR T-cell therapy CTX130 as well as unmet needs within the advanced clear cell renal cell carcinoma patient population, highlighting the phase 1 COBALT-RCC trial (NCT04438083), which is aiming to address these needs.

updated findings from the COBALT-RCC study

. CTX130 is an allogeneic CAR T-cell therapy, akin to other commercially available CAR T-cell products approved for patients with hematologic malignancies, Srour begins. Like typical CAR T-cell therapies, CTX130 uses a chimeric antigen receptor construct aimed at a specific target—in this case, CD70, he reports. What sets CTX130 apart is its status as a generic off-the-shelf product, Srour explains.

To enhance the efficacy of CTX130, investigators incorporated T-cell receptor (TCR) knockout to prevent certain diseases and beta-2 microglobulin knockout to facilitate engraftment without host rejection, he elucidates. Thus, CTX130 encompasses these 3 genetic modifications: CD70 CAR T-cell incorporation, CD70 knockout to prevent cells from killing the CAR T-cell product, and TCR and beta-2 microglobulin knockouts for enhanced engraftment, Srour expands.

Furthermore, in the realm of solid tumors, challenges remain in rendering CAR T-cell therapy effective, he continues, saying that among these hurdles is identifying the optimal target amidst the myriad targets within tumor cells, a task requiring extensive study and research. Additionally, overcoming the suppressive solid tumor microenvironment presents a significant challenge that is distinct from challenges seen with CAR T-cell therapy in liquid tumors, Srour says. Despite these obstacles, progress has been made in recent years toward overcoming these challenges and achieving success in solid tumor therapy, according to Srour. Investigators anticipate continued advancements in the near future, with the hope of replicating the success with CAR T-cell therapy observed in hematologic malignancies, he concludes.

Samer A. Srour, MB ChB, MS, discusses efficacy and safety data for the allogeneic CAR T-cell therapy CTX130 in advanced clear cell renal cell carcinoma.

Dr Srour on the Safety of the Allogeneic CAR T-Cell Therapy CTX130 in Advanced ccRCC

Samer A. Srour, MB ChB, MS, assistant professor, Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses efficacy and safety of the allogeneic CAR T-cell therapy CTX130, which was evaluated in patients with advanced clear cell renal cell carcinoma (ccRCC) as part of the phase 1 COBALT-RCC trial (NCT04438083).

, showed that no dose-limiting toxicities were observed across any of the 4 dose levels administered to patients enrolled on the study (n = 16). Grade 1/2 cytokine release syndrome (CRS) occurred in 50% of patients; however, no grade 3 or higher CRS events were observed. Additionally, no instances of immune effector cell–associated neurotoxicity syndrome (ICANs), graft-vs-host disease, or hemophagocytic lymphohistiocytosis (HLH) were reported. The absence of ICANs and HLH was notable since those toxicities have been commonly associated with CAR T-cell therapies in patients with hematologic malignancies, according to Srour.

Three patients experienced infections that were considered serious, including 1 patient who had grade 5 pneumonia; however, none of these infections were determined to be related to CTX130. Four patients had serious adverse effects related to the CAR T-cell therapy and all were CRS.

Regarding efficacy, 1 patient (6.3%) achieved a complete response (CR) that exceeded 3 years at data cutoff, according to Srour. Although no other responses were reported, 75.0% of patients experienced stable disease (SD), translating to a disease control rate of 81.3%. One patient maintained SD beyond month 12.

Although only 1 response was observed in this cohort of patients, the durable CR serves as a proof of concept for the use of an allogeneic CAR T-cell therapy in patients with ccRCC, Srour explains. Selecting the right target and overcoming the suppressive tumor microenvironment has been a challenge in developing these types of cellular therapies for patients with solid tumors, but the goal remains to continue refining this modality for patients with ccRCC and other histologies, Srour concludes.

Dr Srour on the Safety and Efficacy of the Allogeneic CAR T-Cell Therapy CTX130 in Advanced ccRCC

Samer A. Srour, MB ChB, MS, assistant professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses planned next steps and future avenues of investigation for the novel CD70-targeted agent ALLO-316 in patients with advanced or metastatic clear cell renal cell carcinoma (RCC).

ALLO-316 was investigated in the first-in-human phase 1 TRAVERSE study (NCT04696731). The dose-escalation portion of the study was designed to examine the off-the-shelf CAR T-cell therapy at 4 dose levels of 40 x 10

Initial dose-escalation findings from this trial were presented at the 2023 AACR Annual Meeting

, and showed that the agent had encouraging clinical activity and safety in patients with clear cell RCC who were heavily pretreated and experienced disease progression on standard therapies, Srour states. The agent produced an overall response rate of 17% and a disease control rate (DCR) of 89% in the efficacy-evaluable population (n = 18). Notably, patients with CD70-positive RCC (n = 10) achieved a partial response rate of 30% with the agent, and a DCR of 100%.

For the current analysis, only 2 patients in the study population (n = 19) received the agent at the third dose level. The data that were presented were primarily from patients who received the CAR T-cell therapy at dose levels 1 and 2, Srour notes. Based on these results, the trial will continue to accrue patients from multiple centers, and to administer ALLO-316 at the 2 higher dose levels, he says. Provided that patient outcomes with ALLO-216 continue to be positive, a phase 2 trial could be conducted, Srour continues. Future investigations of this agent will expand to other CD70-expressing solid tumors, he adds.

Although preliminary, these findings renew the hope that CAR T-cell therapy could be an effective option for patients with solid tumors, according to Srour. Therefore, research in RCC and other solid tumors should continue to evaluate the utility of CAR T-cell products such as ALLO-316, he says. These agents have the potential to induce longer, durable remissions for patients with historically poor prognosis, and may eventually lead to a cure for solid tumors, Srour states. Community oncologists are encouraged to refer patients to clinical trials involving this novel strategy, he concludes.

Dr Srour reported receiving honorarium for consulting/speaking for Novartis Pharmaceuticals.

Samer A. Srour, MB ChB, MS, discusses planned next steps and future avenues of investigation for the novel CD70-targeted agent ALLO-316 in patients with advanced or metastatic clear cell renal cell carcinoma. 


Dr Srour on Next Steps Planned for the Investigation of ALLO-316 in Advanced Clear Cell RCC

Samer A. Srour, MB ChB, MS, assistant professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the mechanism of action of ALLO-316, which is being investigated for the treatment of patients with advanced or metastatic clear cell renal cell carcinoma (RCC), and details safety findings from the phase 1 TRAVERSE study (NCT04696731) evaluating ALLO-316 in this patient population.

Preliminary data presented at the 2023 AACR Annual Meeting

 showed ALLO-316 demonstrated antitumor activity and a favorable safety profile. In the efficacy evaluable population (n = 18), the overall response rate (ORR) was 17%, and the disease control rate (DCR) was 89%. Among patients with CD70-positive RCC (n = 10), 3 patients (30%) achieved a partial response, the DCR was 100%, and the median progression-free survival was 5.0 months.

TRAVERSE is a first-in-human study of ALLO-316, which is an off-the-shelf, CD70-targeted CAR T-cell therapy. CD70 is a tumor antigen expressed in several solid tumors and hematologic malignancies, and it is highly expressed in patients with kidney cancer, Srour notes. ALLO-316 is being examined in patients with RCC who have failed the standard therapies, who generally have a poor prognosis, he adds.

Findings from the dose-escalation portion of the trial showed that no unexpected safety signals were reported. One patient treated at the second dose level with conditioning therapy and ALLO-647 experienced a dose-limiting toxicity of grade 3 type 2 autoimmune hepatitis. Additionally, 2 patients had grade 3 neurotoxicity (syncope and fatigue), and 1 patient died due to respiratory failure from COVID-19 infection, which was unrelated to the study treatment.

Cytokine release syndrome (CRS) was manageable, and no instances of immune effector cell–associated neurotoxicity syndrome or graft-vs-host disease were reported.

Many challenges have been faced with the investigation of CAR T-cell therapies in solid tumors, as many of the studies to date have not demonstrated a clinically meaningful benefit. However, ALLO-316 elicited responses in this study, Srour concludes.

Samer A. Srour, MB ChB, MS, discusses the mechanism of action of ALLO-316, which is being investigated for the treatment of patients with advanced or metastatic clear cell renal cell carcinoma, and details safety findings from the phase 1 TRAVERSE study evaluating ALLO-316 in this patient population.


Dr Srour on the Mechanism of Action of ALLO-316 in Metastatic Clear Cell RCC

Samer A. Srour, MB, ChB, MS, assistant professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the study design of the phase 1 TRAVERSE study (NCT04696731), and key data on the use of ALLO-316 in patients with advanced or metastatic clear cell renal cell carcinoma (RCC).

The first-in-human TRAVERSE study utilized a 3+3 dose-escalation design to identify the maximum tolerated dose of the anti-CD70 allogeneic CAR T-cell product ALLO-316 for adults with advanced or metastatic clear cell RCC, Srour begins. A total of 19 patients enrolled on the study received ALLO-316 at escalating dose levels of 40 x 10

 CAR+ cells (n = 2). Prior to ALLO-316 infusion, patients received a daily lymphodepletion regimen consisting of 30 mg/m2 of fludarabine and 300 mg/m2 of cyclophosphamide with or without 10 mg of the anti-CD52 agent ALLO-647, Srour reports. The trial’s primary end point was a target incidence rate for dose-limiting toxicities (DLTs) in the first 28 days after ALLO-316 infusion.

Preliminary efficacy data from this study show that the agent demonstrated both antitumor activity and a favorable safety profile in a heavily pretreated patient population, Srour says. In the efficacy evaluable population (n = 18), the overall response rate (ORR) was 17%, and the disease control rate (DCR) was 89%. This result was more pronounced in the 10 patients with CD70-positive clear cell RCC, who achieved a DCR of 100% and an ORR of 30%, Srour notes.

In terms of safety, the agent’s toxicity profile is comparable to that of autologous CAR T-cell products in this patient population. The regimen elicited one dose-limiting toxicity which was grade 3 type 2 autoimmune hepatitis at the second dose level. There were no reports of immune effector cell–associated neurotoxicity syndrome or graft-vs-host disease. The incidence of cytokine release syndrome (CRS) was predominantly low grade, with 11 patients reporting any-grade CRS and 1 patient reporting a grade 3 or greater CRS event. 

Although these are early findings, they indicate that the regimen may provide a safe and effective option for heavily pretreated patients who historically have poorer prognosis, Srour emphasizes. Moreover, patients show promising responses to lower dose levels of ALLO-316, Srour concludes.

Dr Srour reports receiving honorarium for consulting/speaking for Novartis Pharmaceuticals.

Samer A. Srour, MB, ChB, MS,  discusses the study design of the phase 1 TRAVERSE study, and key data on the use of ALLO-316 in patients with advanced or metastatic clear cell renal cell carcinoma.

Dr Srour on the Phase 1 TRAVERSE Study of ALLO-316 in Metastatic Clear Cell RCC

Samer A. Srour, MB ChB, MS, assistant professor, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses findings with Orca-Q, an investigational therapy consisting of enriched CD34+ stem cells plus T-cell subsets, in patients with high-risk hematologic malignancies eligible for myeloablative conditioning and allogeneic stem cell transplant.

Encouraging interim findings from the first 26 patients treated in the expansion phase of this ongoing, phase 1, multicenter, first-in-human trial (NCT03802695) were presented at the 2023 Transplantation & Cellular Therapy Meetings, Srour says. Transplanting patients with stem cells from a mismatched unrelated or haploidentical donor presents risks for either graft failure, when patients’ bodies reject the graft, or graft-vs-host-disease (GVHD) after engraftment, when the donor cells reject the recipient, Srour explains.

In the 26 patients treated so far in this study, no patients had primary graft failure, Srour notes. At a median of 12 days, all patients had normal neutrophil engraftments, and at a median of 16 days, all patients had normal platelet engraftments, Srour emphasizes.

Additionally, this trial showed low incidences of GVHD, including both acute GVHD and chronic GVHD (cGVHD), Srour says. For example, at a median follow-up of 211 days, the investigators saw no cases of moderate or severe cGVHD, which is encouraging for patients who receive haploidentical transplant, around 24% to 33% of whom can present with cGVHD, even those who receive post-transplant cyclophosphamide, Srour explains. In this study, of the patients with over 3 months of follow-up, one patient had mild cGVHD, Srour notes.

This study also evaluated outcomes with GVHD-and–relapse-free survival (GRFS) at 1 year. At 1 year, 75% of patients were still alive without cancer or major complications such as GVHD, Srour emphasizes. This GRFS rate is favorable compared with those of historical controls, which tend to fall between 40% to 50%, Srour says. These are all positive outcomes for patients treated for high-risk hematologic malignancies, as the patients in this trial are living without disease and with good quality of life, Srour concludes.

This study is sponsored and funded by Orca Bio.

Samer A. Srour, MB ChB, MS, discusses findings with Orca-Q, an investigational therapy consisting of enriched CD34+ stem cells plus T-cell subsets, in patients with high-risk hematologic malignancies eligible for myeloablative conditioning and allogeneic stem cell transplant.

Samer A. Srour, MB ChB, MS

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