Carmen Criscitiello1,2 and Chiara Corti1,2
1Department of Oncology and Haematology (DIPO), University of Milan, Italy
2 Division of Early Drug Development for Innovative Therapy, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20133, Milan, Italy
Correspondence to: Carmen Criscitiello E-mail: carmen.criscitiello@ieo.it
Immunology and oncology have been related since the 19th century, when Dr William Coley reported that killed bacteria inoculated into sites of sarcoma could trigger tumour shrinkage [1]. From that moment, advances in understanding immune surveillance and tumour dynamics have led to fine-tuned therapeutic approaches that are now prescribed in clinical practice or tested in trials.
Tumour microenvironment (TME) is a composite landscape, including cancer cells, fibroblasts, antigen-presenting cells, endothelial cells and a variety of immune cells, potentially able to mount a response against a tumour. Although the release of cancer cell neoantigens triggers and guides anti-tumour immune responses, the onset of inhibitory signals can prevent their development or limit their effectiveness [2]. This dynamic relationship (cancer immunoediting) exposes the immune system's flaws in immune surveillance, after the initial clearance of malignant cells [3]. In fact, the persistence of rare malignant clones (equilibrium phase) paves the way for the acquisition of genetic alterations, responsible of immune evasion and tumour progression [4].
Cancer immunotherapy aims to exploit and reverse the mechanisms of immunologic escape, directly, by putting cancer cells on the firing line or, indirectly, by boosting the accumulation of proinflammatory cytokines, stimulating immunogenic cell death (ICT) and improving T cell infiltration (“hot” TME). The ultimate goal is to promote a better response to immune checkpoint blockade (ICB), one of the most promising therapeutic strategies, to date [5]. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies (mAbs) able to unleash the immune system by preventing a co-inhibitory signal from being sent. The primary targets for ICIs include programmed cell death receptor 1 (PD-1), programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) [5]. Other approaches include cytokines, immune checkpoint agonists, manipulation of T cells, oncolytic virotherapy and vaccines [6]. At present, several clinical trials are evaluating the combination of ICIs and a second complementary strategy [7].
ICIs have been demonstrated to significantly improve outcomes, including overall survival (OS), across several cancer types [8]. As a drawback, the safety profile of ICIs is shaped by a specific spectrum of immune-related adverse events (irAEs) that can vary according to ICI class and to tumour histology [9]. A major issue with immunotherapy is that only a minority of patients derive benefit from such a treatment, even in cancer types traditionally considered immunogenic [6]. Consequently, it is critical to identify predictive biomarkers of response, to accurately select patients who will benefit from immunotherapy and spare the rest from unnecessary toxicity [6]. Among these, PD-L1, exosomal-PD-L1 fraction, tumor-infiltrating lymphocytes (TILs), microsatellite instability (MSI), mismatch repair (MMR) status and tumour mutational burden (TMB) have been widely investigated and a comprehensive approach is looked forward to [10].
Although many cancer types seem to be insensitive to ICIs, others are thought to develop resistance to single-agent immunotherapy. Combination strategies of ICIs with chemotherapy, radiotherapy, targeted therapies, next-generation immune-modulators (NGIMs) or other immune compounds have been conceived in order to boost the immune responses and potentially overcome resistance to ICIs [11, 12]. Some evidence seemed to suggest that both chemotherapy and radiotherapy could be more immunogenic at lower than standard doses, but no comparative trials are available [6]. Optimal doses and timing of administration of such combinations are still uncertain [6].
Though previously tested in the metastatic setting, immunotherapy has been adopted to improve clinical outcomes in the neoadjuvant setting as well, like in triple negative breast cancer (TNBC) [13]. The rationale of using neoadjuvant immunotherapy lies especially on the potential increase of systemic immunity that would improve clinical response of the primary tumor and eradicate residual micrometastatic disease [14]. Promising data from the first prospective phase III, randomized trials assessing neoadjuvant chemotherapy combined with ICIs in patients with early-stage TNBC were reported [13, 15], with demonstration of significantly increased pathological complete response (pCR) rates [13, 15].
In this special issue, clinicians and scientists with expertise in immunotherapy and clinical trials have contributed a series of articles exploring this evolving field. Readers will be accompanied through the current knowledge, ongoing studies and technologies underpinning the immune-oncology landscape. A focus will be put on the novel use of ICIs in the neoadjuvant setting, using TNBC as paradigm. We also look at the techniques and potential benefits of TME manipulation for therapeutic benefit and concentrate specifically on ongoing strategies to potentially overcome cancer resistance to ICB. We hope this special issue will represent a solid introduction and broad overview of immune-oncology research for physicians and researchers who may be less familiar with this novel field.
References
1. Coley W: The treatment of malignant tumors by repeated inoculations of erysipelas: with a report of ten original cases. Am J Med Sci 105, 487-516 (1893).
2. Chen Ds, Mellman I: Oncology meets immunology: the cancer-immunity cycle. Immunity 39(1), 1-10 (2013).
3. Dunn Gp, Old Lj, Schreiber Rd: The three Es of cancer immunoediting. Annu Rev Immunol 22, 329-360 (2004).
4. Efremova M, Finotello F, Rieder D, Trajanoski Z: Neoantigens Generated by Individual Mutations and Their Role in Cancer Immunity and Immunotherapy. Front Immunol 8, 1679 (2017).
5. Pardoll Dm: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12(4), 252-264 (2012).
6. Hegde Ps, Chen Ds: Top 10 Challenges in Cancer Immunotherapy. Immunity 52(1), 17-35 (2020).
7. Zamarin D, Holmgaard Rb, Subudhi Sk et al.: Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med 6(226), 226ra232 (2014).
8. Liu Zb, Zhang L, Bian J, Jian J: Combination Strategies of Checkpoint Immunotherapy in Metastatic Breast Cancer. Onco Targets Ther 13, 2657-2666 (2020).
9. Martins F, Sofiya L, Sykiotis Gp et al.: Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 16(9), 563-580 (2019).
10. Signorelli D, Giannatempo P, Grazia G et al.: Patients Selection for Immunotherapy in Solid Tumors: Overcome the Naïve Vision of a Single Biomarker. Biomed Res Int 2019, 9056417 (2019).
11. Mazzarella L, Duso Ba, Trapani D et al.: The evolving landscape of 'next-generation' immune checkpoint inhibitors: A review. Eur J Cancer 117, 14-31 (2019).
12. Lesterhuis Wj, Salmons J, Nowak Ak et al.: Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity. PLoS One 8(4), e61895 (2013).
13. Schmid P, Cortes J, Pusztai L et al.: Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 382(9), 810-821 (2020).
14. Topalian Sl, Taube Jm, Pardoll Dm: Neoadjuvant checkpoint blockade for cancer immunotherapy. Science 367(6477), (2020).
15. Mittendorf Ea, Zhang H, Barrios Ch et al.: Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet 396(10257), 1090-1100 (2020).
