Intratumoral Injection of Immunotherapeutics: State of the Art and Future Directions

Abstract

Systemic immunotherapies have led to tremendous progress across the cancer landscape. However, several challenges exist, potentially limiting their efficacy in the treatment of solid tumors. Direct intratumoral injection can increase the therapeutic index of immunotherapies while overcoming many of the barriers associated with systemic administration, including limited bioavailability to tumors and potential systemic safety concerns. However, challenges remain, including the lack of standardized approaches for administration, issues relating to effective drug delivery, logistical hurdles, and safety concerns specific to this mode of administration. This article reviews the biologic rationale for the localized injection of immunotherapeutic agents into tumors. It also addresses the existing limitations and practical considerations for safe and effective implementation and provide recommendations for optimizing logistics and treatment workflows. It also highlights the critical role that radiologists, interventional radiologists, and medical physicists play in intratumoral immunotherapy with respect to target selection, image-guided administration, and response assessment.

Graphical abstract

Figure 1:

Diagram of physical properties of tumors. Tumors may possess certain physical properties that present challenges for systemic administration of antitumor agents. These include solid stress, resulting from excessive cell density arising from dysregulated cellular division; tumor stiffness, caused by the presence of a rigid collagen matrix encasing the tumor cells; increased interstitial fluid pressure, which occurs because of leaky vasculature in the tumor, leading to excessive fluid accumulation and an imbalance of fluid inflow and outflow; and irregular tumor microarchitecture, defined as poor cellular organization within the tumor, which impacts the distribution and sequestration of cellular materials. Figure was created with BioRender (https://www.biorender.com/).

Figure 2:

Graph of the number of planned or active clinical trials of intratumoral immunotherapies by treatment class as of June 26, 2023 (source: ClinicalTrials.gov). The following search string was used: intratumoral OR intralesional AND cancer AND immunotherapy. Only trials with the following status are included: recruiting; not yet recruiting; active, not recruiting; or enrolling by invitation. PRR = pattern recognition receptor.

Figure 3:

Clinical examples of intratumoral drug distribution with a radiopaque injection agent. (A) Axial noncontrast CT image in a 61-year-old female patient with uveal melanoma shows ideal distribution of injected drug throughout a liver metastasis, with minimal leakage. (B) Axial noncontrast CT image in a 33-year-old male patient with uveal melanoma shows suboptimal delivery of the same injected drug as in A, with extensive leakage along the needle track (arrow) and outside of the tumor. (C) Axial fluorodeoxyglucose PET image in a 67-year-old female patient with lung cancer shows a lesion in the left lung targeted for intratumoral drug delivery. (D) Axial noncontrast CT image in the same patient as in C shows minimal deposition of the injected drug in the lung tumor, with leakage adjacent to the lesion.

Figure 4:

Diagram of recommendations for standardization of reporting and data collection in clinical trials of intratumoral immunotherapy. These recommendations encompass a multifaceted approach including pharmacokinetics (PK), case report forms (CRFs), photographs, imaging, biopsies, and biomarkers. PD = pharmacodynamics.

Figure 5:

Diagram of multidisciplinary approach to management of an intratumoral immunotherapy program. Clinical trial practitioners have various roles pertaining to separate steps within the intratumoral immunotherapy program and must communicate effectively to achieve a successful workflow with this treatment modality. Clinical coordinators are not directly involved in the outlined steps but oversee several functional aspects of conducting a clinical trial and therefore may work closely with the other identified stakeholders. IR = interventional radiologist, IT = intratumoral, N = nurse, O = oncologist, OI = oncolytic immunotherapy, P = pharmacist, R = radiologist, SCCHN = squamous cell carcinoma of the head and neck.