Cancer vaccines, designed to stimulate anti-tumor immune responses in patients, suffer from notoriously low efficacies in the clinic. In contrast, T cell therapies rely on the generation of de novo immune responses through the transfer of engineered tumor-targeted T cells into patients and are extremely effective in some cancer settings. However, patients’ immune systems often mount responses against these therapeutic T cells, leading to their immunological rejection. In a cheeky ‘when life gives you lemons, make lemonade’ strategy, members of the Riddell Lab in the Clinical Research Division, led by Dr. Joshua Veatch, Fred Hutch physician scientist and practicing medical oncologist at the Seattle Cancer Care Alliance, sought to exploit the immunogenicity of engineered T cells in a new cancer vaccine platform. Their work, recently published in The Journal of Clinical Investigation, reveals that vaccines consisting of T cells engineered to express target antigens successfully elicit robust endogenous immune responses.
Traditional cancer vaccine platforms involve the administration of either peptides, nucleic acids, or recombinant virus vectors encoding tumor associated antigens (TAAs) alongside pro-inflammatory substances, called adjuvants. Adjuvants aid in the stimulation of adaptive T cell and B cell responses against tumors. Unfortunately, in contrast to similarly formulated vaccines against infectious pathogens, cancer vaccines typically do not elicit strong immunity against their targets. This is owed in part to both low immunogenicity of tumors and poor immune function in disease-laden and treatment-bombarded patients. More modern cell-based vaccine approaches involve the transfer of antigen-loaded dendritic cells (DCs) - the poster children of a class of immune cells known as antigen-presenting cells (APCs) that naturally stimulate T cell responses - into patients, in the hopes that they will elicit more effective immune responses. However, these cells are difficult to expand and manipulate in culture and suffer from low viability and variable biodistribution after transfer, presenting significant practical challenges for clinical use.
Adoptive T cell therapies seek to ‘cut out the middleman’, by directly engineering T cells to express tumor-specific receptors, such as chimeric antigen receptors (CARs), and artificially expanding and activating them outside of the body before re-infusing large numbers of these cells into cancer-bearing patients. Frustratingly, components of these engineered cells are often recognized as ‘foreign’ by the immune system, causing immunological rejection of therapeutic T cells, even in immunocompromised patients. T cells are known to traffic efficiently to secondary lymphoid organs, the coordinating centers for adaptive immune responses, and previous work has shown that DCs take up antigens from immunogenic T cells to elicit endogenous T cell responses against them. Hypothesizing that these features might make for an effective vaccine platform, Dr. Veatch and colleagues tested whether T cells engineered to express cancer antigens could elicit productive anti-tumor immune responses.
“It has been noticed that when an immunogenic antigen is genetically inserted into a patient’s own T cells, a powerful T cell response is induced against that antigen, even in patients with severe immune compromise,” explained Dr. Veatch. “In most T cell trials this is undesirable as it leads to immune rejection of the T cells that are intended to serve a therapeutic purpose, but we sought to take advantage of this phenomenon to create a new vaccine platform using T cells modified with cancer antigens to induce and augment T cell responses targeting those cancer antigens.”
To experimentally test the feasibility of a T cell-based vaccine, the group genetically modified T cells to carry model antigens and transferred them into mice. Encouragingly, they observed the expansion of antigen-reactive endogenous T cells in the animals, peaking at 14 days post-vaccination. Additionally, they saw enhanced T cell responses upon re-administration of the vaccine, demonstrating the formation of immunological memory. Using fluorescently labeled engineered T cells to dissect the response further, they found that the vaccine cells migrated to secondary lymphoid organs and were taken up by APCs at those sites, which were in turn able to stimulate antigen-specific T cells in culture.
Next, the Riddell group tested whether the immunogenicity of the T cell-based vaccine could be enhanced through further genetic modifications of the cells to express immunostimulatory molecules, similar in effect to the adjuvants included in traditional vaccine platforms. They tested the inclusion of an array of molecules involved in the maturation of DCs and the activation of T cells. While most adjuvants augmented vaccine-induced immunity, they found that vaccine cells carrying both IL-12 (a cytokine that promotes T cell priming) and GM-CSF (a cytokine that induces the activation of DCs) offered the greatest benefit, with a 25-fold increase in reactive T cell frequency compared to antigen alone.
“In a mouse model, we showed that this approach works by delivering antigens to lymphoid organs throughout the body where they transfer antigens to host dendritic cells that initiate the immune response,” described Dr. Veatch. “We could stimulate even more potent T cell responses to the antigen by combining the antigen with other inflammatory signals in the same vaccine cells, eventually having a version of the vaccine cells that contained antigens and the inflammatory molecules IL-12 and GM-CSF.”
Finally, the investigators utilized a set of preclinical melanoma models to test whether the T cell-based vaccine could induce immune responses strong enough to impact disease progression. They found that the T cell-based vaccine including IL-12 and GM-CSF adjuvants administered shortly after tumor implantation could slow tumor growth and extend the survival of the animals. To study vaccine-induced responses against established cancers, more closely modeling the immune suppressive tumor microenvironments likely to be encountered in the clinic, Dr. Veatch and colleagues treated melanoma-bearing animals after palpable tumors could be detected. In this setting, T cell-based vaccine delivered alone only modestly impacted survival, whereas the co-administration of three additional therapies – the T cell-supportive cytokine IL-2, a PD-1 immune checkpoint inhibitor, and a tumor-reactive antibody – greatly enhanced the efficacy of the treatment.
This work demonstrates that, in addition to tumor-targeted T cell therapies, gene-modified T cells can be used effectively as a cancer vaccine platform. These findings hold the potential to expand the pool of patients who can benefit from currently available immunotherapies. Importantly, the investigators showed that the T cell-based vaccine could readily be produced from human T cells and was capable of stimulating patient-derived antigen-specific T cells, paving a path to clinical translation.
“Mouse models are useful for optimization of a vaccine and understanding mechanisms, but ultimately the true test of a cancer vaccine is how effectively it induces T cell responses to cancer antigens in patients with advanced cancer,” said Dr. Veatch. “We are gearing up for a clinical trial that will vaccinate patients with non-small cell lung cancer against the cancer associated antigen CT83 and hope to eventually target tumor antigens that are personalized to each patient.” Dr. Veatch credited the Fred Hutch Lung Cancer S.P.O.R.E. (Specialized Program of Research Excellence) for supporting this project.
This work was funded by the Lung Cancer Research Foundation, the National Institutes of Health, the Fred Hutch Lung Cancer S.P.O.R.E., the Bezos family, and the Lembersky family.
UW/Fred Hutch Cancer Consortium members Shivani Srivastava and Stanley Riddell contributed to this work.
Veatch JR, Singhi N, Srivastava S, Szeto JL, Jesernig B, Stull SM, Fitzgibbon M, Sarvothama M, Yechan-Gunja S, James SE, Riddell SR. A therapeutic cancer vaccine delivers antigens and adjuvants to lymphoid tissues using genetically modified T cells. J Clin Invest. 2021 Aug 16;131(16):e144195. doi: 10.1172/JCI144195. PMID: 34396986; PMCID: PMC8363286.