Ongoing Investigations of the Use of CAR T-Cell Therapy in Solid Tumors

Dr Hurwitz on Ongoing Investigations of the Use of CAR T-Cell Therapy in Solid Tumors

Michael Hurwitz, MD, PhD, associate professor, internal medicine (medical oncology), Yale School of Medicine, discusses the ongoing investigation into the use of CAR T-cell therapies in patients with solid tumors, such as kidney cancers.

Hurwitz begins by stating that considerations surrounding the use of CAR T-cell therapy in solid tumors, such as renal cell carcinoma (RCC), have been uncertain. The phase 1 COBALT-RCC trial (NCT04438083), which investigated CTX130 allogeneic CRISPR/Cas9–engineered CAR T-cell therapy in patients with advanced clear cell RCC, is currently inactive. However, a new agent with similar attributes to the CAR T-cell product investigated in COBALT-RCC is under development and may improve upon the outcomes seen in COBALT-RCC, Hurwitz begins.

Another trial, the phase 1 TRAVERSE trial (NCT04696731), is ongoing at some sites, he explains. This trial involves off-the-shelf CAR T-cell therapy, Hurwitz explains. These modified CAR T cells are engineered to evade the recipient's immune response and eliminate the need for personalized CAR T-cell production, offering a faster turnaround that is crucial for individuals with advanced solid tumors, Hurwitz explains. Traditionally, introducing foreign T cells into the body triggers immune responses, which are addressed by removing human leukocyte antigens, so the body does not recognize the T cells as foreign. In these modified CAR T cells, the endogenous T-cell receptors are also removed, ensuring these cells do not perceive the body as foreign, he expands.

Along with the FDA approvals of CAR T cells for patients with hematologic malignancies, their application in solid tumors is evolving, Hurwitz emphasizes. Ongoing preclinical research aims to engineer safe, specific, and effective CAR T cells, he states. 

These innovations with CAR T-cell therapy promise highly targeted, safe cancer treatments for patients with solid tumors, Hurwitz continues. Looking forward, the possibility of synergies between CAR T-cell therapy and other treatments looms, he notes. Although the timing of integrating CAR T-cell therapies into the solid tumor treatment armamentarium is uncertain, combining these products with other agents offers a glimpse into a future where cancer treatment is more effective and personalized. In essence, technological advances in cancer therapy are just beginning to unfold, Hurwitz adds. The future promises innovations and a convergence of technologies to reshape cancer treatment, ushering in an era of hope and healing, he concludes.

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Michael Hurwitz, MD, PhD, discusses the ongoing investigation into the use of CAR T-cell therapies in patients with solid tumors, such as kidney cancers.


The Feasibility of Utilizing CAR T-Cell Therapy in Solid Tumors

Dr Hurwitz on the Feasibility of Utilizing CAR T-Cell Therapy in Solid Tumors

Michael Hurwitz, MD, PhD, associate professor, Internal Medicine (Medical Oncology), Yale School of Medicine, discusses the feasibility of utilizing CAR T-cell therapies in patients with solid tumors, such as kidney cancers.

Using CAR T-cell therapies in the realm of solid tumors is associated with greater challenges than using these products in patients with hematologic malignancies, Hurwitz begins. These challenges are primarily attributed to the intricate nature of the solid tumor microenvironment, according to Hurwitz. Unlike liquid tumors that reside in the bloodstream and are easily accessible, solid tumors often present with a more toxic and hypoxic microenvironment, he states. The difficulty lies in reaching these tumors, which may also exhibit increased heterogeneity, Hurwitz adds. CAR T-cell therapies, which are designed to target a specific feature or antigen on tumor cells. When that targeted antigen is lost, these therapies are less effective or entirely ineffective, he notes.

Solid tumors, which are prone to losing specific therapeutic markers, demand careful selection of robust and stable markers, Hurwitz continues. The marker chosen must be abundant on the tumor and resistant to easy loss, a challenging criterion to meet, he says. Another persistent challenge in managing both liquid and solid tumors is the risk of on-target, off-tissue effects, which occur when the targeted antigen that is present on the tumor is also found on healthytissues, Hurwitz explains. This dual presence can result in considerable toxicity, even leading to deaths, as observed in early trials of certain therapies for patients with other diseases, he emphasizes.

For kidney cancer, several issues can arise when targeting markers such as CA9, Hurwitz continues. An initial trial investigating an agent targeting CA9 resulted in overwhelming toxicity, prompting ongoing efforts to refine the approach, he says. Currently, the primary target for kidney cancer is CD70, a well-known and described marker with a history of reliability, Hurwitz says. CAR T-cell therapies are robust killers that surpass previous limitations in specificity and killing ability observed in therapies from earlier treatment eras, Hurwitz concludes.

Michael Hurwitz, MD, PhD, discusses the feasibility of utilizing CAR T-cell therapies in patients with solid tumors, such as kidney cancers.


Michael E. Hurwitz, MD, PhD, associate professor of internal medicine, Yale Cancer Center, compares the utility of antiandrogens in nonmetastatic castration-resistant prostate cancer (CRPC).

In nonmetastatic CRPC, apalutamide (Erleada), enzalutamide (Xtandi), and darolutamide (Nubeqa) are FDA approved antiandrogen therapies. These agents have demonstrated similar clinical activity; however, they have not been compared in head-to-head trials. Notably, apalutamide and enzalutamide are almost structurally identical and share similar toxicity profiles, Hurwitz says.

Conversely, darolutamide is structurally different from apalutamide and enzalutamide and does not cross the blood-brain barrier as readily as the other agents. Patients also seem to experience fewer adverse effects (AEs), such as fatigue, falls, and fractures with darolutamide versus apalutamide and enzalutamide. As such, for patients who are worried about the risk of AEs, darolutamide could be the optimal antiandrogen, Hurwitz concludes.

Michael E. Hurwitz, MD, PhD, compares the utility of antiandrogens in nonmetastatic castration-resistant prostate cancer. 

Dr. Hurwitz Compares the Utility of Antiandrogens in Nonmetastatic CRPC 

Michael E. Hurwitz, MD, PhD, assistant professor of medicine, Yale Cancer Center, discusses the various patient cohorts in the ongoing phase I/II PIVOT-02 trial.

In the phase II portion of the trial, patients with a number of solid tumors will receive the combination of bempegaldesleukin (NKTR-214) and nivolumab (Opdivo). Some of the tumor types that are being evaluated in the trial include melanoma, lung cancer, bladder cancer, kidney cancer, sarcoma, and breast cancer. At the 2019 ASCO Annual Meeting, data for the melanoma and bladder cancer cohorts were presented. In both cohorts, patients received the combination as frontline therapy, says Hurwitz. Notably, in the bladder cancer cohort, only platinum-ineligible patients and those who refused platinum were eligible for enrollment.

In the metastatic melanoma cohort, patients experienced an objective response rate (ORR) >50% and a complete response rate of 34%. In metastatic bladder cancer, the ORR was 44%, which is significantly higher than what is typically seen with nivolumab monotherapy or other immune checkpoint inhibitors, concludes Hurwitz.

Michael E. Hurwitz, MD, PhD, assistant professor of medicine, Yale Cancer, Center, discusses the various patient cohorts in the ongoing phase I/II PIVOT-02 trial.

Michael E. Hurwitz, MD, PhD

Articles

Dr Hurwitz on Ongoing Investigations of the Use of CAR T-Cell Therapy in Solid Tumors

Dr Hurwitz on the Feasibility of Utilizing CAR T-Cell Therapy in Solid Tumors

Dr. Hurwitz Compares the Utility of Antiandrogens in Nonmetastatic CRPC

Dr. Hurwitz on Patient Cohorts in the PIVOT-02 Trial