Editorial: Early Phase Clinical Trials for the Development of Novel Immunotherapeutic Anti-Cancer Agents

Agnese LosurdoAnastasia LaliotiAngelo DipasqualeMatteo Simonelli^*

• Humanitas Research Hospital, Rozzano, Italy

(a) the poten4al iden4fica4on of reliable biomarkers to guide pa4ent selec4on and op4mize 33 treatment strategies, (b) the early detec4on and mi4ga4on of immune-related adverse events 34 (irAEs) and (c) the choice of the op4mal 4ming maximizing immunotherapeu4c strategies 35 36The heterogeneity of tumor-host crosstalk renders a universal biomarker approach unrealis4c. 37 Currently, predic4ve biomarkers such as programmed cell death ligand 1 (PD-L1) expression, 38 tumor muta4onal burden (TMB) and mismatch repair deficiency (dMMR) are rou4nely 39 implemented. However, their performance remains inconsistent, oSen serving be9er as 40 stra4fica4on tools rather than defini4ve predictors of response. For this reason, there is a 41 growing poten4al of minimally invasive biomarkers, including circula4ng tumor DNA (ctDNA) 42 and serum factors to provide early indicators of therapeu4c benefit. Jia et al presented a focus 43 on predic4ve biomarkers for the therapeu4c combina4on of autologous natural killer (NK) 44 cells with PD-1 inhibitor (Sin4limab) in non-small cell lung cancer (NSCLC) pa4ents who had 45 progressed to first-line pla4num-based chemotherapy. A significant associa4on was observed 46 between treatment efficacy and both clearance of ctDNA and higher levels of tumor 47 infiltra4ng PD-L1 + NK cells following treatment, sugges4ng that they may serve as prognos4c 48 On the safety side, although ICIs related toxici4es, which might poten4ally affect every organ 50 and 4ssue, are well noted, accurate predic4on tools remain lacking. This is even more true 51 with immunomodula4ng agents other than ICIs, such as recombinant pro-inflammatory 52 cytokines, which are now a9rac4ng renewed interest in the field of immune-oncology, in 53 monotherapy and in combina4on therapy with other immunomodulatory drugs(5). For 54 instance, Interleukin 2 (IL2) has long been inves4gated as a target cytokine promo4ng T cell 55 expansion, and has been approved for the treatment of metasta4c melanoma and renal cell 56 carcinoma; however, its wide use has been hampered by its toxic profile, with frequent grade 57 3 and 4 adverse effects(6). In this context, Aguirrechu et al conducted a phase I study tes4ng 58 an engineered IL2 protein with an increased affinity for CD8 and NK cells and reduced 59 s4mula4on of regulatory T cells. As a result, a favorable safety profile was reported, dose-60 limi4ng toxicity was not reached and IL2 related severe adverse events (SAEs) (e.g.: vascular 61 leak syndrome and mul4organ dysfunc4on) were not detected, with most frequent toxici4es 62 being the well-known symptoma4c set composed of chills, fever, and tachycardia. 63 3 Lastly, when tes4ng immunomodula4ng agents, we need to consider tumor biology set 64 best 4ming of administra4on; indeed, neoadjuvant immunotherapy has been proven to 65 improve surgical results and overall outcomes, across different tumor types, given the 66 presence of the intact full tumor an4genic repertoire(7). In this background lay both studies 67 presented by two different research groups in esophageal cancer. The clinical of Zhou et 68 al evaluated whether periopera4ve treatment with the an4-PD-1 an4body 4slelizumab, in 69 combina4on with four cycles of neoadjuvant chemotherapy, followed by post-opera4ve 70 adjuvant PD-1 blockade, could improve pathological complete response (pCR) in pa4ents with 71 locally advanced esophageal cancer. The study reported a pCR of 44% and disease-free 72 survival (DFS) of 75% aSer 1 year of follow up. Notably, 16% of the par4cipants enrolled, did 73 not conclude preopera4ve treatment, either due to disease progression or unacceptable 74 toxicity. Most treatment-related adverse events were mild to moderate in severity, including 75 neutropenia, nephrotoxicity, cardiovascular and gastro-intes4nal complica4ons. Overall, the 76 study demonstrated encouraging clinical ac4vity suppor4ng further evalua4on of this 77 periopera4ve combina4on in larger studies. Similarly, the phase Ib/II clinical trial of Zhang et 78 al inves4gated a neoadjuvant regimen that combines chemotherapy with the PD-1 inhibitor 79 4slelizumab as well as the addi4on of low dose radia4on treatment in pa4ents with locally 80 advanced esophageal cancer. The ra4onale stems from the ability of radia4on treatment to 81 reshape tumor microenvironment, crea4ng inflamed and immune-responsive cancer lesions. 82 While this triple-modality approach holds promise for synergis4c efficacy, op4mal radia4on 83 dose needs to be defined, as well as management of overlapping side effects. Defining this 84 therapeu4c balance will be fundamental to ensure improved outcome now offset by 85 treatment related adverse effects. 86Collec4vely, these studies illustrate the mul4faced evolu4on of cancer immunotherapy, 87 emphasizing the importance of integra4ng immune components to enhance checkpoint 88 blockade and fueling immune response. While innova4ve monotherapy and combina4on 89 treatment regimens improve survival, their efficacy remains limited by toxicity risks. Central 90 to these advances is biomarker development, as op4mizing pa4ent selec4on in preclinical 91 trials improves efficacy and mi4gates adverse events. All together such trials reflect a shiS 92 towards precision-guided targeted treatment, poised to redefine the next genera4on of 93 cancer therapy. 94 95