This week we profile a recent publication in The Journal of Clinical Investigation from Dr. Joshua Veatch (pictured, right) and the laboratory of Dr. Stanley Riddell (left) at Fred Hutch and UW.
Can you provide a brief overview of your lab’s current research focus?
My work in the Riddell lab focuses on using T cells specific for neoantigens created by cancer specific mutations to target lung cancer and other solid cancers. One strategy focuses on using “helper” CD4+ T cells specific to tumor antigens to modify the tumor immune microenvironment to make tumors more conducive to treatment with existing immunotherapies. The other approach, which is the topic of this paper, is to augment the T cell response to solid tumors using a novel cellular vaccine platform.
What is the significance of the findings in this publication?
Immune checkpoint inhibitors that target negative regulatory pathways on T cells have clinical efficacy in a broad range of human cancer, but most patients either don’t benefit or respond only transiently to these treatments. In theory, being able to increase the numbers or function of T cells specific for cancer antigens could increase the efficacy of these treatments, but existing vaccine platforms have mostly been ineffective at inducing high level T cell responses to cancer antigens in patients.
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. 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 which we call Tvax.
In a mouse model, we showed that Tvax works by delivering antigens to lymphoid organs throughout the body where they transfer antigens to host dendritic cells that initiate the immune response. We could stimulate even more potent T cell responses to the antigen by combining the antigen with other inflammatory signals in the same Tvax cells, eventually having a version of the Tvax that contained antigens and the inflammatory molecules IL-12 and GM-CSF. This Tvax showed therapeutic efficacy in some mouse cancer models, and showed an ability to induce T cell responses to a broad number of cancer antigens in mice. We showed that we could make similar Tvax cells using human T cells.
What are the next steps for this research?
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. 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. We are also using mouse models to combine vaccination with other immune therapies such as immune checkpoint inhibitors and inflammatory cytokines to increase the anti-tumor efficacy of T cells induced by the vaccine.
If you’d like us to mention your funding sources, please list them.
This work was supported by a young investigator award from the Lung Cancer Research Foundation for myself and a SPORE grant in lung cancer research for Dr. Riddell, as well as generous support from the Bezos and Lembersky families.
