Recent trends in immuno-oncology include novel mouse models, nanoplatforms, and increasingly molecularly homogeneous patient populations in clinical trials.
Paradigm changes in trial design have facilitated faster drug-development models.
Moving forward, an increasing number of preclinical findings will likely translate into clinical success.
The field of immuno-oncology (I-O) has been characterized by both successes and failures. On the positive side, the realization of tumor-infiltrating lymphocytes and the generation of effector T cells expressing chimeric antigen receptors revolutionized the field.
On the other hand, there are some notable setbacks. One of these is the phenomenon of hyperprogressive disease exhibited in a subset of patients who were administered checkpoint blockade immunotherapies. (Though this involves only a minority of patients and is a matter of dispute in some circles). Another is the lack of efficacy of I-O combination therapy in different tumor types.
A brief history of immuno-oncology
Lately, however, the field of I-O has been on fire.
The I-O pipeline consists of nearly 5,000 agents, representing various mechanistic approaches. These advances have led to substantial pharma investment and the application of new approaches for diagnosis and treatment.
The foundations of I-O date back more than a century. A review article published in the Journal of Immunotherapy for Cancer provides a background of the field.
The first attempts to leverage the immune system to treat cancers occurred in 1891, when William Coley tried to treat osteosarcoma with heat-inactivated Streptococcus pyogenes and Serratia marcescens.
In the 1990s, another notable advance came when Allison and colleagues elucidated cytotoxic T-lymphocyte antigen 4 (CTLA-4). In the 2000s, studies by Honjo and colleagues on programmed cell-death protein 1 (PD-1) yielded a new class of anti-cancer agents, the immune checkpoint inhibitors (ICIs). Today, they are used for various types of cancer.
Building a better mouse model
The vast expansion of I-O clinical studies has spurred interest in mouse models with competent immune systems. A burgeoning number of tumor histiotypes are recapitulated by synergistic models. There is also a growing demand for synergistic models with tumors that are cultivated in orthotopic settings, which allows for tumor cells to be surgically implanted into the organ to track tumor growth and treatment response.
The Journal of Immunotherapy for Cancer authors explain that the use of luciferase-expressing cell lines can permit longitudinal, non-invasive small-animal bioluminescence imaging, thus greatly reducing the number of mice needed. It also provides for a semi-quantitative analysis of tumor burden.
These techniques avoid some of the downsides of genetically modified or subcutaneous models, while preserving many of their advantages—such as the tumor microenvironment and an intact immune system—without the problems encountered with some of the humanized mouse models.
The study of tumor immunobiology has been enhanced by the use of organoid technology.
Organoids are three-dimensional in vitro cultures of normal or tumor tissues. They contain multiple cell lineages, such as stem cells and differentiated cells. Organoids also recreate tissue architecture.
Two aspects of organoids make their use promising: Organoids closely resemble the original tumors; and organoids can be cultured from each patient. Experts believe this technology will supplant the use of cell lines during preclinical drug discovery and precision medicine.
Biobanks of cancer organoids are currently being used in clinical trials to pinpoint targetable mutations and to identify patient subgroups. These findings can help stratify patients according to specific anti-cancer options. This approach extends beyond single molecular biomarkers.
Cancer organoids can also function as living surrogates “to use for high-throughput drug screening approaches to aid directly in the treatment of the specific patient that the organoid has been derived from and for the discovery of novel drug and targets. This possibility opens up major possibilities in the selection of personalized treatment options and the prevention of normal tissue toxicity,” according to the authors of a review published in Frontiers in Oncology.
It should be noted that more quantitative data is required to flesh out the predictive value of organoid technology in cancer treatments.
One strategy being studied for delivering immune-targeting molecules directly to solid tumors is through the use of micromachines. These consist of microparticles and organic and inorganic nanoplatforms that have been functionalized with immune agonists.
Writing in Micromachines, researchers explain that co-loading of drugs into a nanocarrier platform can efficiently deliver the drug to the subcellular levels of cancer residing in the tumor microenvironment.
One example of this is a novel nanoplatform called ARAC, which was studied for its potential to enhance survival in NSCLC. ARAC stands for “antigen-release agents and a checkpoint”—in this case, the combination of a PD-L1 antibody and a PLK-1 inhibitor to target immune checkpoint inhibitors.
The nanoplatform is composed of mesoporous silica nanoparticles loaded with the immunotherapy drug volasertib (a PLK-1 inhibitor). To zero in on cancer cells, this agent is functionalized via PD-L1 on the surface of nanostructures.
In their studies in NSCLC, the researchers noted that increased uptake of the nanoparticles via PD-L1 effectively delivered PLK-1 in the cytosol, leading to cellular apoptosis.
In vivo evaluation of ARAC has shown an improved survival rate (up to 30 days) and a three-fold reduction in the tumor volume compared with volasertib. Moreover, the researchers observed that inhibiting PLK-1 resulted in an increase in PD-L1 expression in the remaining surviving cancer cells.
Intriguingly, biocompatible enzymes can be used to power micromotors and deliver specific drugs to specific targets, according to the authors of a review published in Nano-Micro Letters. Enzyme-powered micromotors have several advantages over catalytic motors, such as bioavailability and biocompatibility. One example of an enzyme-powered micromotor designed for improved anti-cancer drug delivery involves a solid silica core coated with urease enzymes and a mesoporous silica shell, which offers a high loading capacity of doxorubicin.
Even in ionic media, the urease enzymes-modified nanomotors convert chemical energy to mechanical work, which boosts their potential for in vivo use. In preclinical studies, the nanomotors-based Dox-loaded system honed in on HeLa cells. This increased affinity stems from a synergistic effect of enhanced drug release and ammonia derived from high levels of the urea substrate.
"Increased drug delivery efficiencies achieved by these nanomotors may have potential for use in future biomedical applications."
— Authors, Nano-Micro Letters
Smaller patient subsets
Identifying the genomic features of various cancers has been aided by the decreased cost of—and greater access to—next-generation sequencing and other high-throughput diagnostics.
Consequently, cancer patients have become fragmented into smaller groups, allowing for specific biomarker-positive subpopulations to be recruited into I-O clinical trials.
I-O trials are now more molecularly homogeneous, with smaller patient sample sizes.
One study found that the mean number of patients per oncology trial decreased to 129 in 2019 from 429 in 2014. On the flipside, the number of I-O trials worldwide has ballooned and is currently pegged at about 6,000 studies.
Speedy drug development
The time to clinical development of new anti-neoplastic agents has dropped during the past few decades. Nowadays, targeted agents can achieve fast-tracked FDA approval based on phase 2 trial results.
A paradigm shift has occurred in I-O clinical trials, toward a “seamless” trial: an initial, small, phase 1 study, subsequently enlarged by different expansion cohorts, and even randomized arms. This type of trial structure can result in accelerated FDA approval.
An example of this strategy in action was KEYNOTE-001, the first-in-human pembrolizumab trial. This trial, involving 1,260 patients, was the basis for this immune checkpoint inhibitor’s approval for melanoma and NSCLC indications.
With the I-O paradigm shift, biologic timelines for approval have been reduced from about 10 years to fewer than 5 years.
Specifically, median drug development times are now 112.7 months for cytotoxic therapies, 87.1 months for targeted nonprecision therapies, and 64.6 months for precision strategies.
What this means for you
The current era of I-O has demonstrated the increased importance of linking preclinical with clinical research. There has also been an increased focus on clinically relevant biomarkers that monitor and predict tumor responses. The trajectory for I-O developments will further incorporate translational and reverse translational approaches to improve trial design and execution, thus potentially increasing the efficacy of novel therapies and combined therapies developed with I-O.