As the new Editor-in-Chief and Deputy Editor-in-Chief for the Journal for ImmunoTherapy of Cancer (JITC), we thought it appropriate to pay attention to current issues that confront our patients, scientists, and practitioners as we navigate the next era in the immunotherapy of cancer. We would particularly like to take this opportunity to thank Drs Pedro J Romero and James L Gulley for shepherding JITC to this point along with the extraordinarily talented editorial board and amazing staff who made, and still make, it possible.

As the official journal of the Society for Immunotherapy of Cancer (SITC), we find that our vision for the journal’s role in accelerating scientific advancement in the field aligns with SITC’s renewed strategic vision1 for the Society and its stakeholders in many ways. Here, we highlight a few areas where JITC can help play a role in the future of cancer immunotherapy and continue to serve as the premier, open-access journal addressing issues of importance—both existing and emerging—throughout the entire translational research spectrum from basic tumor immunology to clinical practice.

A bigger tent for our field

The apparent ‘calling’ and then mastering of two fields—immunology and oncology, now ‘IO’—is indeed challenging and not for the faint of heart. This is particularly important in understanding the Janus-like reciprocal Darwinian selection of both the tumor and the immune response, a process that may have gone on for a decade in patients before they see a physician.

We believe that the time is now ripe to bring in other disciplines involved in ‘learning’, and adopting them to our Journal, including neurobiology,2 artificial intelligence/machine learning (AI/ML), and endocrinology3 in their intersections with IO. We would also like to call out to those working in imaginative biotech to publish their work rather than keep the results in the drawer of their desks. It may bring many benefits to early industry, including: (1) De-risking investment by having vetted science peer-reviewed and published as part of the so-called ‘Critical Path’; (2) shining a bright light on the knowns and the ‘unknown unknowns’ by formalized reports with suitable scientific controls more rapidly advancing science for all; and (3) promoting a work culture that values the contributions of all of the individuals realized in publications, helping to foster their careers. We commend to you, our portal.

New therapies, new approvals

We used to say that IO, which was once referred to as biologic therapy, was concerned with therapies from the cell membrane out, including cytokines and their receptors, antibodies, and, of course, cell therapies. Now that immune checkpoint blockade clearly adds to conventional small molecule-based treatments for patients with melanoma and lung cancer but not all tumor types,4 we should widen our therapeutic armamentarium. We would like to renew the call from SITC for 100 new IO agents approved for the treatment of cancer patients in the next decade. This will require diligence, discerning the best and most important science, as well as its translation to the clinic with robust and rigorous clinical trials.5 The field is likely to benefit from new developments in small molecule inhibitors, with several of them now in the clinic, designed to enhance immunity.6 We also like the idea of inviting those with targeted protein degraders and other small molecule designer drugs,7 and modern tumor-infiltrating lymphocyte therapies8 focused on enhancing tumor immunity to JITC. We renew the call to identify those biomarkers that are essential to be included in clinical trials of IO agents, and to identify and explore those with promise, revealing biology and mechanism of action.

Tumor immune cycle

The definition of a cyclic process in which tumor-specific T-cell immunity is stimulated and kills tumors, almost in perpetual motion, is likely only partially complete. Several studies promote the need for coordinated responses of various immune cells within the tumor microenvironment for therapeutic success, indicated by terms such as ‘immune contexture’ or ‘ecosystems’. Despite this, less attention has been paid to these other cells whose provenance has been overshadowed by the partiality of T-cell therapies. Over the last couple of years, we have witnessed the appearance of apparent requirements for various leukocyte populations, previously found to be tumor-promoting, in the execution phase of tumors following T-cell-based therapies.9–11 This calls for their reappreciation when evaluated in an immunotherapeutic setting.

Antigen-specific therapies

Tumor recognition and distinction from normal cells is at the heart of immunotherapy. The overwhelming evidence of the importance of neoantigen-specific T cells in tumor immunity has increased interest in therapies to promote neoantigen-specific immunity, and, as such, rejuvenated interest in cancer vaccines. With the strength of a fully focused biotechnology industry, it is possible to rapidly define and produce patient mutation-specific vaccines, the use of which has shown promise in patients with pancreatic cancer12 and melanoma.13 It immediately puts forward questions concerning its feasibility and affordability in a real-world setting. Should we shy away from it, focusing more on shared tumor-associated antigens to promote the tumor immune cycle and ignite spontaneous neoantigen-specific immunity?14 Will it be vaccines, bispecific antibodies, cytokines, or T-cell receptor-based therapies that will emerge as most effective, or is the maximum efficacy only obtained when all such approaches are combined?15 Can single targets suffice, or do we need multiple targets (many hits on goal)? We believe this Journal should support the exploration of these notions in detail.

Tumor micro-environment and macro-environment

New technical developments have made it possible to study the tumor anatomy and its surroundings in detail, down to the transcriptomic profile of single cells in their spatial context. It is impossible to comprehend the vast amount of data created by these new techniques without the help of AI/ML. Specifically, AI’s ability to use all publicly available single-cell full transcriptome data sets will be a great help in defining the functional cell states of single cells identified by single-cell spatial transcriptomic techniques. While being galvanized by the level of detail provided by these modern ‘omics’, we also observe a tsunami of Systems Immunology (SI) studies reaching conclusions based solely on bioinformatic approaches. Here, it is good to step back a bit and ask ourselves, what are they bringing conceptually, and can we truly understand what the data is telling us? Sometimes, it is old wine in new bags (same conceptual findings but now with extremely detailed data sets). In other cases, new insights are provided that may advance the field.

It is here where we see a struggle between conventional reductionistic science and SI. What experiments will show that what we deduce from the ‘omics is true, and how are we able to do so? How will we be able to prove that, indeed, this is what we need to know beyond the confirmation and association in other patient cohorts? We welcome discussion of these questions that our readers and the greater cancer immunotherapy community face with critical experiments designed to test the interface of SI and reductionistic science.

Clinical trials

The value of preclinical experiments in rodents allows the exclusion of ineffective agents and a deep understanding of a new therapy’s mechanism(s) of action. Importantly, many clinical trials offer similar opportunities. In this instance, one collects the biological materials from the blood, tumor, lymph nodes and potentially derived early passage tumor and normal tissue organoids from the patients involved. The new technological possibilities allow us to answer more questions with a deeper understanding of the responses of patients. Hence, insights beyond the primary objectives may be obtained from these early phase trials, also when the outcomes are negative. We strongly welcome clinical trial reports supported by in-depth translational studies as this should propel the clinical development of new therapeutics/strategies as well as honor the patients bold enough to participate.

That the field of IO is still open and needs clarity and further study is without doubt. We hope to engage the field, find what is true and defensible, and always promote a rigorous and robust search for understanding the biology of epithelial and hematologic proliferation gone astray with immune therapies that enable true progress in the field. Indeed, we are at your service. Please send us your best work and we promise to be true to our collective calling.

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Acknowledgments

The authors wish to thank SITC staff including JITC Managing Editor Andrea Kunz for editorial assistance and review.