Expanding Cancer Immunotherapy by Exploiting Recall Immunity – A New Co-Therapy Option for Checkpoint Inhibitors

Immune checkpoint inhibitors (CIs) have emerged as a revolutionary treatment for several cancer types. They enhance immune recognition by silencing checkpoints and allowing T-cells to attack tumor cells. Despite the significant improvement in prognosis for some cancer patients, there are challenges in using CIs for the treatment of all cancers.

For example, CIs do not work well on immune-cold tumors, which are tumors that are not inflamed, thereby eliciting an insufficient response from the immune system. They are also not as effective in tumors with low mutational burden, due to the dependence on tumor “self” antigens for immune recognition. Therefore, there is a need for a solution to improve the efficacy of CIs to make them applicable to the entire cancer patient population.

To address this challenge, SRI International has developed a novel immunotherapy that is capable of delivering previously encountered antigenic peptides specifically to cancer cells and facilitating their presentation through the MHC class I pathway. This new therapy utilizes a synthetic nanoparticle delivery system comprising three components: a neutral stealth liposome, encapsulated synthetic immunogenic HLA class I restricted peptides derived from the measles virus (MV), and a tumor-targeting peptide on the external surface of the liposome.

The targeting peptide results in accumulation of the liposomes specifically inside cancer cells, and facilitates presentation of the MV-derived immunogenic peptides specifically in HLA class I molecules. SRI International refers to this system as, “Targeted Antigen Loaded Liposomes” (TALL). Therefore, TALL can generate a strong secondary immune response specifically against the targeted tumor cells in a patient who has been previously vaccinated against, or infected by, MV.

In short, the strategy is attempting to trick the immune system into responding as though the cancer cell is infected with MV without the use of a viral particle. SRI International has shown that treatment with TALL alone substantially reduces the growth of lung, triple-negative breast, and pancreatic tumors in mice.

TALL has distinct advantages when compared to other immunotherapies:

1)     It bypasses the need to identify tumor-associated antigens or educate the immune system through a primary immune response

2)     It is anticipated to be effective against tumors with a low mutational load, making it efficacious in both early-stage and metastatic cancer

3)     It does not use live virus, viral subunits or biologically derived material, allowing for complete synthetic manufacturing

As TALL can provide a potent synthetic antigen specifically to tumor cells, it can turn immune-cold tumors into immune-hot tumors to elicit a robust immune response. SRI International has conducted pilot studies to determine the efficacy of combining TALL with the anti-PD1 checkpoint inhibitor. Their results using the combination therapy showed at least a 10-fold reduction in tumor burden in mice bearing orthotopic breast and pancreatic tumors, respectively, when compared to using CI treatment alone. The combination treatment also successfully prevented metastasis from occurring.

Register for this webinar to learn about how TALL can successfully be used in combination with existing immunotherapies, like checkpoint inhibitors, to generate a robust cytotoxic T lymphocyte response directed specifically against the tumor, resulting in a drastic reduction of tumor burden.

Speaker

Indu Venugopal, Bioresearch Scientist, SRI International

Dr. Venugopal received her PhD in Bioengineering from the University of Illinois at Chicago, where she studied drug delivery to the central nervous system using magnetic nanoparticles. In 2017, she joined Dr. Kathlynn Brown’s R&D group at SRI International to work on the Fox Three program, which is focused on using highly specific cell-binding ligands for targeted delivery of therapeutics. As a Senior Scientist, she currently leads the TALL immunotherapy research project at SRI in which pseudo-viral-infected cells are used as a novel immunotherapy for treating various cancers.

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