Trial watch: intratumoral immunotherapy

Abstract

While chemotherapy and radiotherapy remain the first-line approaches for the management of most unresectable tumors, immunotherapy has emerged in the past two decades as a game-changing treatment, notably with the clinical success of immune checkpoint inhibitors. Immunotherapies aim at (re)activating anticancer immune responses which occur in two main steps: (1) the activation and expansion of tumor-specific T cells following cross-presentation of tumor antigens by specialized myeloid cells (priming phase); and (2) the immunological clearance of malignant cells by these antitumor T lymphocytes (effector phase). Therapeutic vaccines, adjuvants, monoclonal antibodies, cytokines, immunogenic cell death-inducing agents including oncolytic viruses, anthracycline-based chemotherapy and radiotherapy, as well as adoptive cell transfer, all act at different levels of this cascade to (re)instate cancer immunosurveillance. Intratumoral delivery of these immunotherapeutics is being tested in clinical trials to promote superior antitumor immune activity in the context of limited systemic toxicity.

Tumor response assessment on imaging following immunotherapy

“…The tumor is therefore used as its own vaccine by eliciting polyclonal B- and T-cell mediated adaptive immune responses against pre-existing tumor-specific and tumor-associated antigens, that produce abscopal effects in distant, non-injected (“anenestic”) tumor sites ( 23 ). For instance, as the first HIT-IT for IIIb-IVM1a melanoma, the herpes-derived genetically modified oncolytic virus called Talimogene laherparepvec (T-VEC) was recently approved by the Food and Drug Administration/European Medicines Agency ( 25 – 27 ). In addition, there is (pre)clinical evidence that intratumoral injections of mAbs directed against CTLA-4 and/or PD(L)-1 might enable to overcome resistance to systemic ICIs by inducing an effective intratumoral T-effector cell homing ( 28 – 31 ).…”

“…In addition, there is (pre)clinical evidence that intratumoral injections of mAbs directed against CTLA-4 and/or PD(L)-1 might enable to overcome resistance to systemic ICIs by inducing an effective intratumoral T-effector cell homing ( 28 – 31 ). Many other drugs are currently under investigation to treat several solid tumors ( 27 ). Anticipating the increased use of HIT-IT, specific imaging criteria, the intratumoral RECIST (itRECIST), have been developed for response assessment.…”

Chemo-immunoablation of solid tumors: A new concept in tumor ablation

“…Immune checkpoint inhibitors have revolutionized the landscape of tumor immunotherapy, and the anti-tumor effects of intratumoral applications, in particular, have been demonstrated in numerous preclinical trials. Recently, there have been many clinical trials focusing on the clinical application of intratumoral immune checkpoint inhibitors with encouraging preliminary results, including the phase I clinical trial of cemiplimab, an intratumoral anti-PD-1 agent (NCT03889912), and the phase I clinical trial of Nivolumab, an intratumoral anti-PD-1 agent (NCT03316274), Phase II and Phase III clinical trials of the intratumoral anti-PD-1 drug ipilimumab or Nivolumab in combination with the anti-CTLA-4 drug Ipilimumab (NCT04090775, NCT03755739), anti-CD40 inhibitor Selicrelumab in combination with the anti-PD-L1 inhibitor Atezolizumab (NCT03892525) and other ( 56 ). For patients with allogeneic transplants, intratumoral anti-PD-1 treatment combined with TLR9 agonist can ensure a strong anti-tumor immune response while avoiding severe transplant rejection caused by systemic immunotherapy, reflecting the unique effectiveness and safety of intratumoral injection ( 57 ).…”

In vivo fate and intracellular trafficking of vaccine delivery systems

“…Intratumoral route has been emerging for administration of tumor vaccines. In 2015, intratumorally administered talimogene laherparepvec was approved for oncolytic virotherapy by the FDA for melanoma treatment [117] . After intratumoral injection, nanovaccines with tumor antigens can be taken up by APC in tumor microenvironments.…”