Biotech breakthroughs in immunotherapy
Key Takeaways
Advances in immunotherapy are now targeting broader patient populations.
New research revolves around LabVax 3(22)-23, which targets Lab-positive metastatic or recurrent adenocarcinoma of any primary tumor site after standard-of-care therapies. In cases of colorectal cancer, researchers are supplementing the microbiome to trigger immune response.
Oncologists should follow cancer vaccines, microbiome-based strategies, and novel validation techniques for advances in the effective treatment of their patients.
The advent of immune checkpoint inhibition, chimeric antigen receptor T-cell therapy, and cancer vaccination have advanced cancer research by leaps and bounds. Nevertheless, these advances fall short in the effective treatment of most cancer diagnoses.
Breakthroughs in other modalities of immunotherapy offer enhanced options in the treatment of an increasing array of cancer types.[]
Vaccine research
Researchers hypothesize that vaccination vs labyrinthin (Lab), a novel tumor-specific protein expressed on the cell surface of most adenocarcinomas of various cancer types, may prompt strong immune responses against Lab-positive adenocarcinomas in cancer patients.
LabVax 3(22)-23 consists of four synthetic Lab-based peptides developed to induce both B-cell and T-cell responses.
A phase 1 trial has assessed the feasibility and safety of administering LabVax 3(22)-23 and adjuvant GM-CSF sargramostim in 10 patients with Lab-positive metastatic or recurrent adenocarcinoma of any primary tumor site after standard-of-care therapies.[]
The patients received GM-CSF subcutaneously and LabVax 3(22)-23 intradermally on weeks 1, 2, 4, 8, and 12. They were then followed every 3 months for 1 year post-treatment. The primary objective was to determine toxicity per CTCAE V5.0.
Median age of the patients was 52 years. They had diagnoses of colon, rectum, ovarian, or scalp cancer and had received a median number of four prior lines of systemic therapy. The treatment was well tolerated.
Two patients completed all five treatments, exhibiting stable disease and optimal tumor response; RNA sequencing analysis of peripheral blood mononuclear cells of these patients revealed that LabVax 3(22)-23 had modulated the activity of immune cells and the PD-1 pathway. Overall, seven patients discontinued treatment secondary to tumor progression. OS has yet to mature.
Further study of this treatment is planned, according to the researchers. “Based on preclinical synergism with pembrolizumab, this dose and injection schedule will be tested in a phase II open label study of LabVax 3(22)-23 and GM-CSF in combination with pembrolizumab in patients with refractory lung adenocarcinomas and adenocarcinomas of all other tumor types,” they study authors concluded.
Investigating the microbiome
Leveraging recent discoveries regarding the human microbiome and its role in disease, investigators at the biotech start-up Recolony identified specific strains of bacteria that exist in lower numbers in patients with colorectal cancer than in healthy individuals.[]
Using animal models, the researchers discovered that supplementation with these bacteria can induce an antitumor immune response in colorectal cancer, as well as melanoma, breast cancer, and lung cancer.
“Our results show enhanced immune cell activation and infiltration into the tumor when the bacteria are applied,” the company stated on their website. “This way, we aim to circumvent the problem of current immunotherapies, by which tumors with low immune-cell infiltration cannot be effectively treated.”
Because this therapy is derived from commensal bacteria that are naturally present in the gut, the treatment is expected to be very safe and tolerable. The bacteria are applied in lyophilized form packed in pH-resistant capsules, taken orally. The researchers suggest that the bacterial supplementation will improve treatment efficacy and quality of life for patients with cancer.
Proof of concept efficacy in colorectal cancer has been achieved via in-vivo models, and a phase 1b study in humans is slated for the second half of 2025. Recolony plans to extend this microbiome approach to other cancer types. The scientists have isolated a separate microbial-derived product which they anticipate has the potential to be a biomarker for the early detection of colorectal cancer and therapy efficacy.
In other research, a 2023 study found that patients with NSCLC stage IV who received antimicrobial therapy during the month before checkpoint inhibitors had a decreased PFS compared with that of patients who were given checkpoint inhibitors sans AMT (14 vs 4 months, P = 0.002). Notably, the antimicrobial therapy used disrupted the microbiome.[]
Validating tools
Efficient CAR therapies aimed at CD19 B-cell malignancies have transformed the field of cell-based immunotherapy.
Writing in BMC Biotechnology on the subject of CAR T-cell therapeutic validation, researchers explain that the majority of in-vitro validation strategies depend on 2D systems.[] These systems, however, do not properly account for solid tumor challenges. Typically, 2D in vitro systems include a mixture of CAR T-cells and target cancer cell lines as monolayers to gauge the functionality and specificity of these effector cells.
“Although these strategies are important and vital steps of the pre-clinical development, they do not take complex morphology and three-dimensional (3D) organization of the cancer cells into consideration," the researchers write. "Cancer cells cultured in 3D systems, referred to as spheroids, acquire new phenotypic traits through changes in gene expression profile which might influence the recognition by redirected effector cells.” (See diagram here.)
Spheroids are better represented in in-vitro models vs standard 2D systems. Spheroids also predict in-vivo studies, which are the final step in the validation process of any CAR. Using organoids (a type of spheroid) in studies is difficult and costly, however.
As an alternative, the researchers developed a simple and affordable method to develop cysts. These cysts, which contain a hollow lumen, afford more 3D complexity than a simple spheroid.
The cysts were tested using clinically validated CAR redirected T-cells by transducing Caco-2 cells with the CD19 gene. The researchers demonstrated that CD19CAR T-cells were able to kill these cells either as a 2D monolayer or as cysts. They also showed that this method applies to various techniques, including super-resolution microscopy, high-throughput live imaging, and bioluminescence assays.
“Such flexibility permitted a complete characterization of the cyst structure as well as a quantitative and qualitative description of CD19 CAR T-cell cytotoxicity and ability to extravasate through complex matrices,” the researchers reported. “This protocol represents a step between classical spheroids and more complex organoids while being scalable, inexpensive, reliable and easy to adapt to various environments and quantifications methods.”
What this means for you
The expanding field of immunotherapy is sizzling with recent advances in cancer vaccines, microbiome-based strategies, and novel validation techniques. Oncologists should be encouraged by new potentials in treating an increasing number of cancers thanks to such advancements, with more breakthroughs on the horizon.