Immunotherapy in the fight against solid tumors

Since William Coley first attempted to harness the immune system in 1891 to treat bone cancer, immunotherapy has been explored in the treatment of many types of cancer – both solid and liquid – and has revolutionized and rejuvenated the field of oncology.

However, although certain immunotherapy treatments have shown great promise, such as the use of CAR-T cell therapy for fluid tumors, the success of cancer immunotherapy in solid tumors is still limited, presenting a major challenge in the field of immuno-oncology.

This is because solid tumors come with several treatment barriers, including an immunosuppressive microenvironment that dampens the immune response, inefficient trafficking, and tumor antigen heterogeneity.

According to Andrew Scharenberg, MD, co-founder and chief executive officer (CEO) of Umoja Biopharma, one of the main obstacles – especially when developing CAR-T therapy – is that the dense tumor microenvironment comprises diverse populations. cells that do not all share a uniform biomarker. This made finding one individual target very difficult.

“In solid tumors this is one of the main challenges, given the need to target different areas of the tumor, such as tumor-associated macrophages that help protect cancer cells from the immune system, cancer-associated fibroblasts that create the cellular structures built up by tumors. on, and neo-vascular which supply the tumor with the nutrients it uses for continued growth,” says Scharenberg.

Despite the challenges, there is a continuing stream of research underway to improve immunotherapy treatments for solid tumors, which is not surprising given that approximately 90% of cancers are mature, with some highly aggressive and invasive cancers developing drug resistance to more conventional therapies, such as chemotherapy.

There are currently several types of immunotherapies being used or being developed for solid tumors – from tried and tested immune checkpoint inhibitors to CAR-T cell therapies being explored in clinical trials – in hopes of addressing the challenges mentioned above.

Immune checkpoint inhibitors: a revolution in cancer treatment

The discovery of the immune checkpoint protein marked a major breakthrough in tumor immunotherapy. After the approval of the first immune checkpoint inhibitor, ipilimumab – a monoclonal antibody drug that activates the immune system by targeting the CTLA-4 protein – in 2011, others followed suit, leading to immune checkpoint inhibitors emerging as a revolutionary cancer treatment in the last decade. .

Prior to this, the state of solid tumor immunotherapy was in a dire situation, relying on immunocytokines such as interleukin-2 or alpha-interferon, which were neither very effective nor highly toxic. In addition, clinical trials for various types of cancer vaccines eventually found most vaccines to be ineffective.

But now, thanks to the initial success of immune checkpoint inhibitors, immunotherapy has regained some ground, and immune checkpoint inhibitors have been used to treat many types of cancer, most notably melanoma and Hodgkin’s lymphoma. This has resulted in better survival outcomes for cancer patients.

This type of immunotherapy works by blocking a checkpoint protein from binding to its partner protein on tumor cells, which prevents a ‘die’ signal from being sent to T cells, thereby allowing them to actually recognize and destroy cancer cells.

Most immune checkpoint inhibitors act against the CTLA-4 or PD-1 checkpoint proteins, as well as against PD-L1, which is a 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 have their drawbacks. Primary and acquired resistance to these drugs can be quite common, with insufficient antitumor T cells, inadequate cell function, and impaired formation of memory T cells all being contributing factors to resistance mechanisms.

In addition, infiltration of myeloid-derived suppressor cells (MDSCs) – a heterogeneous population of immature cells that can suppress the immune response and develop during cancer – at sites of tumor growth inhibits the expansion and function of anti-cancer CD8+ T cells, even in the face of post inhibitors. immune check.

Fortunately, research is being done to counteract this mechanism. For example, researchers at the Roswell Park Comprehensive Cancer Center in the US recently identified a novel approach that could enhance the efficacy of immune checkpoint inhibitors, with preclinical findings demonstrating that brequinar differentiation agents effectively target MDSCs and significantly enhance immune checkpoint inhibitor responses. .

The promise of CAR-T cell therapy for blood cancer: could it also be used to treat solid tumors?

As previously mentioned, CAR-T-cell therapy – which uses genetically altered T cells to fight cancer – has been shown to be highly effective in treating fluid tumors, and since 2017, six CAR T-cell therapies have been approved by the Food and Drug Administration (FDA). . FDA) for the treatment of blood cancers, including lymphoma, some forms of leukemia, and multiple myeloma.

However, we have yet to see approval of 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 Center for Cellular Immunotherapy, is not currently in late-stage clinical trials either.

“Key stumbling blocks are the lack of good target antigen in solid tumors which results in ‘off-target, off-tumor toxicity’ in which healthy tissue is damaged, and the immunosuppressive tumor microenvironment which tends to kill T cells,” says Sheppard.

But findings from a recent study, of which Sheppard is a co-author, have offered potential strategies for enhancing T-cell therapy in solid tumors. The study investigated two interfering genes – Regnase-1 and Roquin-1 – that regulate inflammatory responses in T cells, to determine whether inflammatory activity in solid tumor models could be enhanced.

“For this study, we used the well-known CRISPR/Cas9 system to genetically disable these genes and compared the differences between interfering with them individually or together in engineered T cells currently being clinically evaluated against solid tumor antigens. We measured its function using in vitro and animal models, and found that while interfering with this gene alone somewhat enhanced antitumor function, interfering with both genes simultaneously increased engineered T-cell function in animal models and led to near-complete tumor clearance in one of ours. model,” explained David Mai, first author of the study.

Findings suggesting that the combined disruption of Regnase-1 and Roquin-1 is a viable strategy for enhancing the function of solid tumor-targeting CAR T cells that is currently under clinical investigation. Mai said that with the development of clinical methods to interfere with endogenous genes, Regnase-1 and Roquin-1 have the potential to be clinically disrupted in therapeutic CAR T cell products against solid tumor antigens.

Currently, there are many trials testing CAR T therapy in solid tumors. “In addition to work in our study, various approaches are being developed including combinations with immune checkpoint inhibitors, oncolytic viruses, vaccines encoding CAR target antigens, and the use of dominant negative receptors or ‘switches’ that block suppressor signals such as PD. -L1 or TGF-beta or turn it into a stimulation signal,” says Sheppard.

“While these developments will take time to come to fruition, several promising candidates and approaches have already entered clinical trials and if a signal is seen, the development pathway could be very short, allowing CAR-T cells to be approved for solid tumors for the first time. .”

He added that ultimately he believes cellular immunotherapy holds great promise, due to the fact that cells are complex and can be programmed with “software” to enable them to meet multiple challenges, producing smart drugs capable of tackling solid tumors.

An interesting range of immunotherapeutic approaches

There is great hope about the future of immunotherapy for solid tumors, with a broad spectrum of immunotherapies to target different types of solid tumors, namely in the form of cell therapies, immune checkpoint inhibitors, and vaccines.

One company using a new approach to CAR T-cell therapy is Umoja Biopharma. While most CAR T cell therapies are currently engineered ex vivo – which can be time-consuming and very expensive – Umoja’s VivoVec platform is designed to manufacture CAR T cell therapies in vivo; in other words, inside the patient’s own body.

“This means no shipping and logistics to a centralized factory, no months of waiting, and a reduced complexity of the overall administrative experience. The hope is a means to deliver life-saving cell therapies at lower cost, faster speed, and wider reach,” said Scharenberg.

Umoja’s UB-VV200 solid tumor program combines three technologies to attack tumors: the VivoVec™ delivery system that enables the engineering of CAR T cells directly in the patient’s body; a receptor called RACR™ is added to CAR T cells promoting T cell persistence and cell survival; and TumorTags™, designed to enable CAR T therapy to recognize different parts of the tumor microenvironment for precise targeting.

Meanwhile, cancer vaccines are also currently in development, including new mRNA vaccines for solid tumors, such as BioNTech’s FixVac candidate, BNT111, for the treatment of advanced melanoma. The company’s FixVac platform uses fixed combinations of mRNA-encoded tumor-associated antigens that aim to trigger a robust 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 inoperable anti-PD1-refractory/relapsed stage 3 or 4 melanoma. The vaccine has received orphan drug designation and fast-track status from the FDA.

In fact, we may not have to wait long for effective cancer vaccines to become commonplace. Thanks to the success of the COVID-19 vaccine, some researchers say that 15 years of progress was achieved within 12 to 18 months. Moderna’s chief medical officer – who also develops cancer vaccines – Paul Burton, recently stated that the company hopes to offer personalized cancer vaccines against various types of tumors by 2030.

Plus, there’s even a new type of immune checkpoint blocker called LAG-3 inhibitors, which were 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 proof that they initiated an attack on cancer cells but failed, making them interesting target to explore.

With a large amount of research being carried out in all areas of oncology, research around the use of immunotherapy for solid tumors is continuously expanding in scope, which, looking into the future, could signal a positive outlook for the treatment of many types of cancer. cancer.