From the Clinic to the Lab: Overcoming Resistance to Immune Checkpoint Therapy

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As a result of breakthroughs in immune checkpoint inhibitors over the past decade, immunotherapy has joined surgery, radiation therapy, and chemotherapy as one of the pillars of cancer treatment. However, nearly half of patients still do not benefit from immune checkpoint blockade.

During the 2022 Society for Immunotherapy of Cancer (SITC) Annual Meeting Keynote Address, Padmanee Sharma, MD, PhD, Professor of Genitourinary Medical Oncology and Immunology, and Director of Scientific Programs for the James P. Allison Institute at The University of Texas MD Anderson Cancer Center, Houston, discussed ongoing research to overcome mechanisms of resistance to immune checkpoint therapy and to improve clinical outcomes.1

“Multiple immune checkpoints exist, and combinations are the future,” said Dr. Sharma. “Because [immune checkpoints] are dynamic, however, we must study both pre- and on-treatment human tumor samples to guide therapeutic decisions and to make rational decisions about combinations. The organ-specific microenvironment also needs to be considered to understand what type of immune responses are occurring within those organs,” she added.

Padmanee Sharma, MD, PhD

Padmanee Sharma, MD, PhD

Research Questions Remain

As Dr. Sharma explained, U.S. Food and Drug Administration (FDA) approvals for immune checkpoint therapy have come “quickly” over the past decade in multiple tumor types, including melanoma, lung cancer, renal cell carcinoma, and hepatocellular carcinoma. By targeting the immune system and the immune response rather than the cancer cell, she said, immunotherapy has been able to generate tumor eradication across different tumor types, regardless of the cell of origin.

Nevertheless, numerous research questions remain. The combination of immune checkpoint inhibitors to treat advanced melanoma, for example, has led to responses in up to 60% of patients, but understanding about why some patients respond and others do not is still lacking. In addition, there are questions about the potential for biomarkers to enable patient selection for treatment to improve response rates and minimize immune-related adverse events. Researchers are continuing to look for pathways that may be targeted to improve clinical outcomes.

According to Dr. Sharma, a search of revealed nearly 3,000 ongoing clinical trials involving an immune checkpoint inhibitor. However, she adds, it is critical to integrate laboratory work into clinical research and translate from the clinic to the lab (ie, reverse translation).

“In this setting, patients are polymorphic, and the disease is heterogeneous,” Dr. Sharma explained. “We must generate hypotheses from the clinical data sets…take those data back to the laboratory, and in the appropriate immunocompetent model, test our hypotheses to understand deeper mechanisms that can lead to the next generation of clinical studies.”

Neoadjuvant Immunotherapy

This is precisely the approach that Dr. Sharma and colleagues have taken in the setting of neoadjuvant clinical trials since 2006, prior to any FDA approvals of an immune checkpoint therapy agent. “We had to call it presurgical and not neoadjuvant because these drugs were not approved by the FDA,” she said. “But we designed our studies in the neoadjuvant fashion because we wanted to have access to tumor tissues and move immune checkpoint therapy to an earlier disease setting.”

In patients with localized bladder cancer, investigators were able to identify T cells expressing inducible co-stimulator (ICOS) as a novel subset of cells that expanded after treatment with anti–CTLA-4 monotherapy, while also demonstrating a pathologic complete response rate of 25%.2,3 In a second neoadjuvant trial, investigators demonstrated a pathologic complete response of 37.5% with combination anti–CTLA-4 plus anti–PD-L1 immune checkpoint therapy. Interestingly, however, in patients with large, bulky disease, whose disease tends to recur after surgery, the pathologic complete response rate was 42%.4

Gene-expression analysis comparing tumor samples before and after treatment showed the top 10 genes were related to the immune pathway. According to Dr. Sharma, this is not surprising, considering the increase in infiltrating immune cells. What was surprising, however, was the increase in the ICOS pathway.

Based on these results, Dr. Sharma and colleagues hypothesized the ICOS and ICOS ligand pathway could be targeted and developed as a combination therapy strategy. In collaboration with the lab of James Allison, PhD, at MD Anderson Cancer Center, the investigators used combination therapy to target both ICOS and CTLA-4 in wild-type and ICOS-knockout murine models. Results of the study showed a significant improvement in survival in wild-type mice who received combination therapy compared with any monotherapies for the untreated mice.5

Resistance to Immune Checkpoint Therapy

As Dr. Sharma explained, however, not all tumor types are equally responsive to immune checkpoint therapy. To better understand the mechanisms of resistance within the tumor microenvironment, Dr. Sharma and colleagues conducted another neoadjuvant clinical trial in patients with localized prostate cancer.

After two doses of anti–CTLA-4 therapy prior to surgery, investigators observed a significant increase in infiltrating immune cells within the previously “cold” tumor microenvironment. However, they also saw an increase in PD-L1 and VISTA inhibitory pathways.6

In the subsequent CheckMate 650 trial, the combination of both anti–CTLA-4 and anti–PD-1 in patients with metastatic castration-resistant prostate cancer led to clinical responses.7 However, investigators also observed a higher frequency of adverse events among patients receiving combination immune checkpoint therapy.

“It is very important for us now to think about new dosing and scheduling to hopefully maintain efficacy yet minimize toxicity,” said Dr. Sharma. These analyses are still ongoing.

Another tumor type with strong resistance to immune checkpoint therapy is glioblastoma. A comparison of glioblastoma with non–small cell lung cancer, renal cell carcinoma, colorectal cancer, and prostate cancer identified a significantly higher frequency of CD73-positive and CD68-positive cells within the glioblastoma microenvironment than in the other tumor types—even after treatment with anti–PD-1 therapy.8

“This subset of macrophages was found to be very immunosuppressive within the glioblastoma microenvironment. That led us to hypothesize that blockade of this subset may help to improve responses to immune checkpoint therapy,” stated Dr. Sharma. In fact, a preclinical model demonstrated long-term survival in 50% of CD73-knockout mice who received combination anti–CTLA-4 and anti–PD-1 therapy.

“These data are very encouraging and suggest that CD73 is another target in patients with glioblastoma,” she noted.

Finally, based on preclinical data showing that resistance to anti–CTLA-4 therapy was associated with an increase in the EZH2 pathway,9 Dr. Sharma and colleagues have designed a clinical trial to study an EZH2 inhibitor in combination with anti–CTLA-4 therapy. “Hopefully, we’ll see better immune responses here and understand the potential mechanisms of response and resistance by collecting the samples,” she added. This clinical trial is ongoing.

The Era of Immune Checkpoint Therapy

In the past, chemotherapy and targeted therapy have not shown significant benefit when combined with surgery for patients with stage IV metastatic disease, highlighting the lack of benefit associated with debulking surgery. In the era of immune checkpoint therapy, however, Dr. Sharma highlighted the chance to change how stage IV disease is treated by considering the combination of immune checkpoint therapy plus debulking surgery in the setting of solid tumors.

“In this new era [of immune checkpoint therapy], it is possible that surgery may lead to antigen release, which then may allow for responses to be generated and maintained with immune checkpoint therapy and to have memory response,” she explained.

“Removing a large lesion in a debulking surgery and leaving smaller lesions behind could allow for immune checkpoint therapy and immune responses then to get rid of all that disease,” she continued. Dr. Sharma presented safety data and encouraging survival data based on ad hoc analyses of a clinical trial in which patients with metastatic renal cell carcinoma received immune checkpoint therapy followed by debulking surgery and then continued therapy with an anti–PD-1 antibody after surgery. These data led her to hypothesize that debulking surgery in the era of immune checkpoint therapy may provide clinical benefit, and she concluded by saying, “It may be time for us to consider revisiting debulking surgery in the age of immunotherapy with a prospective study.” 

DISCLOSURE: Dr. Sharma reported financial relationships with Achelois, Adaptive Biotechnologies, Affini-T, Apricity, Asher Bio, BioAtla, BioNTech, Candel Therapeutics, Carisma Therapeutics, Catalio, Codiak, C-Reveal, Dragonfly, Earli, Enable Medicine, Glympse, Hengenix, Hummingbird, ImaginAb, Infinity Pharma, JSL Health, Lava Therapeutics, Lytix, Marker, Oncolytics, PBM Capital, Phenomic Al, Polaris Pharma, Sporos, Time Bioventures, Trained Therapeutix, Two Bear Capital, Venn Biosciences, Inimmune, and Xilis.


1. Sharma P: Immune checkpoint therapy: Identifying mechanisms of response and resistance. 2022 SITC Annual Meeting. Session 202: Keynote Address. Presented November 11, 2022.

2. Liakou C, Kamat A, Tang DN, et al: CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci 105:14987-14992, 2008.

3. Carthon B, Wolchok JD, Yuan J, et al: Pre-operative CTLA-4 blockade: Tolerability and immune monitoring in the setting of a pre-surgical clinical trial.Clin Cancer Res 16(10): 2861-2871, 2010.

4. Gao J, Navai N, Alhalabi O, et al: Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med 26:1845-1851, 2020.

5. Fan X, Quezada SA, Sepulveda MA, et al: Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy. J Exp Med 211:715-725, 2014.

6. Gao J, Ward JF, Pettaway CA, et al: VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 23:551-555, 2017.

7. Sharma P, Pachynski RK, Narayan V, et al: Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: Preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell 38:489-499.e3, 2020.

8. Goswami S, Chen Y, Anandhan S, et al: ARID1A mutation plus CXCL13 expression act as combinatorial biomarkers to predict responses to immune checkpoint therapy in mUCC. Sci Transl Med 12(548):eabc4220, 2020.

9. Goswami S, Apostolou I,  Zhang J, et al: Modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy. J Clin Invest 128: 3813-3818, 2018.