A SITC vision: adapting clinical trials to accelerate drug development in cancer immunotherapy

Abstract

Clinical trials of cancer immunotherapy (IO) were historically based on a drug development paradigm built for chemotherapies. The remarkable clinical activity of programmed cell death protein 1/programmed death ligand 1 blockade, chimeric antigen receptor-T cells, and T cell engagers yielded new insights into how the mechanistic underpinnings of IO are reflected in the clinic. These insights and the sheer number of novel immunotherapies currently in the pipeline have made it clear that our strategies and tools for IO drug development must adapt. Recent innovations like engineered T cells and tumor-infiltrating lymphocytes demonstrate that immune-based treatments may rely on real-time manufacturing programs rather than off-the-shelf drugs. We now recognize adoptively transferred cells as living drugs. Progression criteria have been redefined due to the unique response patterns of IO. Harnessing the power of both biomarkers and the neoadjuvant setting earlier in drug development is of broad interest. The US Food and Drug Association is increasingly impacting the design of trials with respect to dose optimization and clinical endpoints. The use of novel endpoints such as pathologic complete/major response, treatment-free survival, and minimal residual disease is becoming more common. There is growing acceptance of using patient-reported outcomes as trial endpoints to better measure the true clinical benefit and impact of novel IO agents on quality of life. New opportunities created by modern data science and artificial intelligence to inform and accelerate drug development continue to emerge. The importance of streamlining the clinical research ecosystem and enhancing clinical trial access to facilitate the enrollment of diverse patient populations is broadly recognized. Patient advocacy is critical both to drive the science of IO, and to promote patient satisfaction. To capitalize on these opportunities, the Society for Immunotherapy of Cancer (SITC) has established a goal of at least 100 new, unique IO approvals over the next 10 years. Accordingly, SITC has developed initiatives designed to integrate the viewpoints of diverse stakeholders and galvanize the field in further adapting clinical trials to the unique features of IO, moving us closer to our ultimate goal of using IO to cure and prevent cancer.

Keywords: Adoptive cell therapy - ACT; Biomarker; Immune Checkpoint Inhibitor; Patient reported outcome - PRO; Tumor microenvironment - TME.

Figure 1. Cancer immunotherapy landscape. The cancer immunotherapy landscape is rapidly evolving. Current FDA-approved options include vaccine therapies, adoptive cell therapy, ICIs, TCEs and cytokines. The deployment of immunotherapies with novel mechanisms of action supported by sophisticated biomarker assessments (figure 4) is expanding the repertoire of treatment options for patients, with the potential for more tailored immunotherapy treatment plans. Created in BioRender. Staff, S. (2025) https://BioRender.com/n80v366. FDA, Food and Drug Administration; ICI, immune checkpoint inhibitor; mRNA, messenger RNA; NK, natural killer; TCE, T-cell engager.

Figure 2. Current clinical development paradigms. (A) There is increasing interest in identifying individuals at high risk for cancer development who are healthy, or who have premalignant lesions likely to progress to frank malignancy. Here, clinical trials aim to either prevent cancer outright, or to intercept the progression of high-risk precancerous lesions to overt malignancy. The endpoints for clinical trials of immune interception or prevention strategies include the incidence or (re-)occurrence of high-risk premalignancy or overt cancer. (B) Historically, immunotherapies have first been tested in patients with metastatic disease. Recently, clinical trials have increasingly focused on testing immunotherapies in early-stage disease, particularly the neoadjuvant setting. Here, immunotherapies may have the greatest clinical impact, as disease burdens and tumor-associated immune suppression are lower, and patients have been exposed to fewer drugs that may adversely impact host immunity. Thoughtful drug development strategies are required to safely and effectively flip the script of drug development for cancer immunotherapies. To this end, emerging surrogate clinical endpoints that are both patient-centric and reflect survival benefits should both modernize and accelerate the development of effective immunotherapies for patients. Created in BioRender. Staff, S. (2025) https://BioRender.com/f08g904. ctDNA, circulating tumor DNA.

Figure 3. Dose-toxicity relationships. Shown are examples of dose-toxicity relationships for cytotoxic (traditional) anti-cancer agents and other agents that do not require dosing to a toxic level to achieve anti-cancer activity (flat or shifted curves). The horizontal line at 0.20 reflects the acceptable dose-limiting toxicity. DLT, dose-limiting toxicity.

Figure 4. Cancer immunotherapy biomarkers. A variety of biomarker analyses that assess DNA, RNA, and protein can be performed on biopsies of the primary tumor, TDLN, sites of metastasis, and/or blood samples. Emerging methods allow for minimally invasive biomarker assessments and include liquid biopsies, molecular imaging and radiomics. Ultimately, it is likely that distinct technologies will be combined to generate composite biomarkers that most accurately reflect the active tumor-immune dynamic within a given patient. The present and future landscape of immunotherapy biomarker analyses is represented by this theoretical circos plot, which highlights both the potential and likely complexity of future biomarker assessments. Created in BioRender. Staff, S. (2025) https://BioRender.com/o83j407. cfDNA, cell-free DNA; cfRNA, cell-free RNA; ctDNA, circulating tumor DNA; IHC, immunohistochemistry; Met, metastatic; RNA-seq, RNA sequencing; TDLN, tumor draining lymph node.