Efforts are Underway to Tackle Immunotherapy Resistance in Refractory RCC

Increasing cancer antigen presentation as well as working with tumor cells in and delivering novel cells to the microenvironment may help in overcoming mechanisms of immune checkpoint inhibitor resistance in refractory renal cell carcinoma.

During the 2023 Genitourinary Cancers Symposium, CancerNetwork® spoke with Tian Zhang, MD, MHS, regarding efforts to overcome mechanisms of resistance to immune checkpoint inhibitors in patients with recurrent renal cell carcinoma (RCC) beyond the second line of treatment.

According to Zhang, an associate professor in the Department of Medicine at Harold C. Simmons Comprehensive Cancer Center of the University of Texas Southwestern Medical Center, several strategies are being assessed to mitigate immune checkpoint resistance in patients who have received first-line immunotherapy. These include increasing cancer antigen presentation as well as working with tumor cells in or administering novel cells to the microenvironment.

In her presentation at the meeting, Zhang highlighted a phase 1/2 study (NCT03530397) investigating bispecific MEDI5752 as a strategy for overcoming resistance mechanisms in patients with advanced tumors. Investigators reported that MEDI5752 elicited an overall response rate of about 58% in the immunotherapy-naïve population; in the presentation, Zhang noted that more time was needed to determine how the refractory population will respond to treatment.


When we’re thinking about immune checkpoint resistance, there are a lot of great people thinking about this problem because it is quite an important problem in patients who have had first-line immunotherapy options and are developing resistance and disease growth.

Multiple ways to tackle mechanisms of resistance are underway, whether that’s through increasing cancer antigen presentation, working with the cells in the microenvironment, or even delivering novel cells into the tumor microenvironment. There are many early phase studies that are looking at these possibilities to tackle these mechanisms of resistance.

If we’re not curing enough patients in the frontline setting with the currently available or next generation immunotherapy treatments, for example, we will be looking more and more at patients who have refractory disease to frontline therapies.

Developing novel agents and strategies to overcome those mechanisms of resistance are going to be very important. I think there are some exciting targets for bispecific [antibodies] and cellular therapies like CAR T cells, [which] have made a difference in hematologic malignancies. [They] are starting to make their way into solid tumors and, in particular, kidney cancer.


Albiges L, Rodriguez LM, Kim S, et al. Safety and clinical activity of MEDI5752, a PD-1/CTLA-4 bispecific checkpoint inhibitor, as monotherapy in patients (pts) with advanced renal cell carcinoma (RCC): preliminary results from an FTIH trial. J Clin Oncol. 2022;40(16):107-107. Doi:10.1200/JCO.2022.40.16_suppl.107

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