Ever since William Coley first attempted to harness the immune system in 1891 to treat bone cancer, immunotherapy has been explored in the treatment of various different cancers – both solid and liquid – and has revolutionized and rejuvenated the field of oncology.
However, despite certain immunotherapy treatments having shown very promising results, such as the use of CAR-T cell therapy for liquid tumors, the success of cancer immunotherapy in solid tumors has been limited, presenting big challenges within the immuno-oncology field.
This is because solid tumors come with several treatment barriers, including an immunosuppressive microenvironment that dampens immune response, inefficient trafficking, and heterogeneity of tumor antigens.
According to Andrew Scharenberg, M.D., co-founder and chief executive officer (CEO) of Umoja Biopharma, one of the main obstacles – particularly when developing CAR-T therapies – is that the microenvironment of solid tumors is made up of a diverse population of cells that do not all share uniform biomarkers. This makes finding one individual target extremely difficult.
“In solid tumors, this is one of the major challenges, given the need to target different areas of the tumor, like tumor associated macrophages which help shield cancerous cells from the immune system, cancer-associated fibroblasts which create the cellular structure a tumor builds upon, and the neo-vasculature which supplies the tumor with nutrients it uses for continued growth,” said Scharenberg.
Despite the challenges, there is a continuous stream of research being conducted to improve immunotherapy treatments for solid tumors, which comes as no surprise given they account for approximately 90% of adult cancers, with some types of highly aggressive and invasive cancers developing drug resistance against more conventional therapies, such as chemotherapy.
There are currently several types of immunotherapy being used or developed for solid tumors – from tried and tested immune checkpoint inhibitors to CAR-T cell therapies that are being explored in clinical trials – in the hope of overcoming the aforementioned challenges.
Immune checkpoint inhibitors: a revolution in cancer treatment
The discovery of immune checkpoint proteins marked a major breakthrough in tumor immunotherapy. After the approval of the first immune checkpoint inhibitor, ipilimumab – a monoclonal antibody medication that activates the immune system by targeting the protein CTLA-4 – in 2011, others followed, leading to immune checkpoint inhibitors emerging as the revolutionary cancer treatment of the last decade.
Before this, the state of solid tumor immunotherapy was in a dire situation, relying on immunocytokines like interleukin-2 or alpha-interferon, which weren’t very effective and were also highly toxic. Moreover, clinical trials for different types of cancer vaccines eventually found the vaccines to be mostly ineffective.
Now, though, thanks to the initial success of immune checkpoint inhibitors, immunotherapy has regained its spark, and immune checkpoint inhibitors have been used to treat a wide range of cancers, most notably melanoma and Hodgkin’s lymphoma. This has resulted in improved survival outcomes for cancer patients.
This type of immunotherapy works by blocking checkpoint proteins from binding with their partner proteins on tumor cells, which prevents an ‘off’ signal from being sent to the T cells, thereby allowing them to actually recognize and destroy the cancer cells.
Most immune checkpoint inhibitors either act against the checkpoint proteins CTLA-4 or PD-1, as well as against PD-L1, which is the partner protein of PD-1. And, more recently, immune checkpoint inhibitors are also being developed targeting LAG-3.
However, currently approved immune checkpoint inhibitors do come with their drawbacks. Primary and acquired resistance to these drugs can be fairly common, with insufficient antitumor T cells, inadequate function of these cells, and impaired formation of memory T cells all being contributing factors to resistance mechanisms.
Furthermore, the infiltration of myeloid-derived suppressor cells (MDSCs) – a heterogeneous population of immature cells that can suppress immune responses and expand during cancer – at tumor growth sites blocks the expansion and function of anti-cancer CD8+ T cells, even in the face of immune checkpoint inhibitors.
Fortunately, research is being conducted to counteract these mechanisms. For example, researchers at Roswell Park Comprehensive Cancer Center in the U.S. recently identified a novel approach that could improve the efficacy of immune checkpoint inhibitors, with preclinical findings demonstrating that the differentiation agent brequinar effectively targeted MDSCs and significantly improved immune checkpoint inhibitor response.
The promise of CAR-T cell therapy for blood cancer: could it also be used to treat solid tumors?
As mentioned previously, CAR-T cell therapy – which uses genetically altered T cells to fight cancer – has proven to be very effective in treating liquid tumors, and since 2017, six CAR T cell therapies have been approved by the Food and Drug Administration (FDA) for the treatment of blood cancers, including lymphomas, some forms of leukemia, and multiple myeloma.
However, we are yet to see the approval of a CAR T cell therapy for the treatment of solid tumors and, according to Neil Sheppard, Head of the T Cell Engineering Lab at the University of Pennsylvania’s Center for Cellular Immunotherapies, there are currently none in late stage clinical trials either.
“The key stumbling blocks have been a lack of good target antigens in solid tumors resulting in ‘on-target, off-tumor toxicity’ where the healthy tissue is damaged, and the immunosuppressive tumor microenvironment that tends to shut T cells down,” said Sheppard.
But the findings of a recent study, of which Sheppard was a co-corresponding author, have offered a potential strategy to improve T cell therapy in solid tumors. The study investigated disrupting two genes – Regnase-1 and Roquin-1 – that regulate inflammatory responses in T cells, in order to determine whether inflammatory activity in solid tumor models could be boosted.
“For this study, we used the well-known CRISPR/Cas9 system to genetically knockout the function of these genes and compared the differences between disrupting them individually or together in engineered T cells that are currently being clinically evaluated against solid tumor antigens. We measured their function using both in vitro and animal models, and found that while disrupting these genes alone somewhat increased antitumor function, disrupting both genes simultaneously starkly improved the function engineered T cells in animal models and led to almost complete tumor clearances in one of our models,” explained David Mai, the study’s first author.
The findings showed that combined disruption of both Regnase-1 and Roquin-1 is a feasible strategy to improve the function of existing CAR T cells targeting solid tumors that are currently under clinical investigation. Mai said that with growing clinical methods to perturb endogenous genes, Regnase-1 and Roquin-1 could potentially be clinically disrupted in a therapeutic CAR T cell product against solid tumor antigens.
Currently, there are numerous trials underway testing CAR T therapies against solid tumors. “Aside from the work in our study, various approaches are being advanced including combination with immune checkpoint inhibitors, oncolytic viruses, vaccines encoding the CAR target antigen, and the use of dominant negative or ‘switch’ receptors that either block suppressive signals such as PD-L1 or TGF-beta or convert them into stimulatory signals,” said Sheppard.
“While these developments will take time to come to fruition, multiple promising candidates and approaches have entered clinical testing and if signals are seen, the development path could be quite short, allowing CAR-T cells to be approved for solid tumors for the first time.”
He added that ultimately he believes cellular immunotherapy holds a great deal of promise, due to the fact that cells are complex and can be programmed with “software” to enable them to counter a variety of challenges, resulting in smart medicines that are able to tackle a solid tumor.
An exciting pipeline of immunotherapy approaches
There is a lot to be hopeful about regarding the future of immunotherapy for solid tumors, with a vast array of immunotherapies in the pipeline to target different types of solid tumors, namely in the form of cell therapies, immune checkpoint inhibitors and vaccines.
One such company making use of a novel approach to CAR T cell therapy is Umoja Biopharma. While most CAR T cell therapies are currently engineered ex vivo – which can take a significant amount of time and be extremely costly – Umoja’s VivoVec platform is designed to manufacture CAR T cell therapy in vivo; in other words, inside of the patient’s own body.
“This means no shipping and logistics to a centralized manufacturing plant, no months of waiting, and a reduction in the overall complexity of the administration experience. The hope is a means to deliver life-saving cell therapy at a lower cost, faster speed, and broader reach,” said Scharenberg.
Umoja’s UB-VV200 solid tumor program combines three technologies to attack the tumor: the VivoVec™ delivery system that enables the engineering of CAR T cells directly in the patient’s body; a receptor called RACR™ added to the CAR T cells that promotes T cell persistence and cell survival; and TumorTags™, which are designed to allow the CAR T therapy to recognize different parts of the tumor microenvironment for precise targeting.
Meanwhile, cancer vaccines are also heavily in development at the minute, including novel mRNA vaccines for solid tumors, such as BioNTech’s FixVac candidate, BNT111, for the treatment of advanced melanoma. The company’s FixVac platform utilizes a fixed combination of mRNA-encoded, tumor-associated antigens aiming to trigger a strong and precise immune response against cancer.
BNT111 is currently being investigated in a phase 2 trial in combination with the PD-1 inhibitor cemiplimab in patients with anti-PD1-refractory/relapsed unresectable stage 3 or 4 melanoma. The vaccine has received orphan drug designation and fast track status from the FDA.
In fact, we might not have that long to wait until effective cancer vaccines become commonplace. Thanks to the success of the COVID-19 vaccines, some researchers say that 15 years’ worth of progress has been unspooled in 12 to 18 months. The chief medical officer of Moderna – which is also developing cancer vaccines – Paul Burton, recently stated that the company expects to be able to offer personalized cancer vaccines against multiple tumor types by 2030.
Moreover, there is even a new type of immune checkpoint inhibitor called a LAG-3 inhibitor, which was approved by the FDA last year. Just like CTLA-4 and PD-1, LAG-3 is another checkpoint on the surface of T cells. According to research, LAG-3 shows signs of activation and exhaustion, which is evidence that they started an attack on cancer cells but failed, making them an attractive target to explore.
With such a huge amount of research being done on all frontiers of oncology, research surrounding the use of immunotherapy for solid tumors is constantly growing in scope, which, looking to the future, could signal a positive outlook for the treatment of many different types of cancer.
New technologies related to immunotherapy in the fight against solid tumors (Powered by IN-PART)
- Targeting ART1 to Overcome Immune Resistance in Lung Cancer – Institute of Cancer Research (ICR)
- Novel Small Molecule Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (TDP1) for Treatment of Solid Tumors – National Cancer Institute