Research

Learn more about the Translational Tumor Immunology Lab's work and impact.

Lab materials
Lab materials
Lab materials

Translational Tumor Immunology Lab Overview

Current work in the Translational Tumor Immunology Lab spans three important areas in cancer immunology:

  • Novel expansion and activation strategies for T-cell adoptive immunotherapy
  • New approaches to combining T-cell- and B-cell-based strategies to stimulate both cellular and humoral immune responses
  • Further optimizing cancer stem cell (CSC) vaccines to specifically target this cell population.

Taking new directions is imperative to improve antitumor immunity and prolong survival in cancer.

Strategies

The Translational Tumor Immunology Lab is advancing CSC immunity and cancer immunotherapy to overcome existing obstacles in several ways.

Cancer Stem Cell (CSC) Vaccine: CSC-specific Peptide Delivery by Nanoparticle

Since the demonstration of our CSC-dendritic cell (DC) vaccine in 2012, we continue to look for new ways to lessen constraints. Early work required tumor tissue samples from which to isolate CSCs in order to prepare cell lysates for exposure to antigen-presenting cells, e.g. DCs. This approach, however, is challenging for clinical translation since it requires patient-specific tumor (from which to isolate the CSCs) and blood samples (from which to derive dendritic cells).

Our current work overcomes these limitations by using the biomarker aldehyde dehydrogenase (ALDH) to identify CSCs. The CSC-derived ALDH peptides can be sensitized easily, and it eliminates the need to isolate CSCs from patient tumor tissue since the peptide — the antigen — is common among multiple cancer types and can be sensitized as “off-the shelf” product.

In addition, our collaboration for investigation of a nanoparticle delivery system eliminates the need to generate dendritic cells from patient blood. The nanoparticle delivery system we are working with has been used to deliver chemotherapy for some time, but our collaboration research represents the first use of the platform to deliver CSC peptides to induce immunity against CSCs in cancer immunotherapy.

These advances help make the vaccine feasible for clinical translation as an off-the-shelf therapy for treating many types of cancers in combination with conventional treatments.

To date, we have demonstrated efficacy of the vaccine in small animal models and we’re currently conducting toxicity testing in preparation for clinical trials.

Further Exploration of B Cells & Antitumor Immunity

Our current work continues to expand our understanding of the role B cells play in the immune response to cancer, a role that has been underappreciated until recently. Our research builds on our previous findings showing B cells are key players in humoral immunity against cancer, and that the combination of humoral and cellular immunity further improves the antitumor response. We continue to identify the mechanisms of B-cell anticancer immunity and the mechanisms that regulate it.

Results

Our investigations have led to findings that advance our understanding of tumor immunity and cancer immunotherapy. Key discoveries include:

T-cell Role in Anticancer Immunity

Early work demonstrated, in vitro and in vivo, several methods to sensitize and expand tumor-reactive T cells for adoptive immunotherapy in cancer using monoclonal antibodies and recombinant cytokines. We focused primarily on CD3/IL-2 signaling as well as co-stimulatory signals for T-cell proliferation and differentiation, such as CD28, CD40L, and 4-1BB. We also identified and characterized, using several strategies, tumor-specific subsets of T cells.

B-cell Role in Anticancer Immunity

Expanding our efforts to what we hypothesized was an underrecognized role of B cells in cancer immunity, we were the first to demonstrate that in vivo sensitized and in vitro activated B cells could mediate tumor regression in cancer adoptive immunotherapy. More specifically, we showed in vivo that B cells in fact play multiple roles in cancer immunity: as antigen-presenting cells, as producers of antibodies, and as tumor-killer cells similar to T cells. Prior to our findings, T cells were believed to be the only killer cells involved in anti-tumor immune responses.

Cancer Stem Cell–Dendritic Cell Vaccines

Our laboratory was the first to report the immunogenicity of cancer stem cells, a “milestone” immunological strategy that brought together two highly promising areas in cancer research: cancer stem cells and immunotherapy. In animal models, we demonstrated efficacy as well as certain mechanisms of a vaccine made from purified cancer stem cells (CSCs) delivered by antigen presenting cells. The vaccine targeted CSCs, and we demonstrated both a significant protective as well as therapeutic efficacy in combination either with conventional therapy or with the immune checkpoint inhibitors, such as PD-L1 and/or CTLA-4.

Clinical Relevance & Impact

Work in the Translational Tumor Immunology Lab may one day soon impact the care surgeons and other specialists with adjunctive immunotherapeutic strategies to treat patients with cancer.

Future Directions

As we look ahead, our focus centers on two main areas: identifying additional mechanisms underlying the antitumor response of B cells, and toxicity testing in nonhuman primates in preparation for clinical trials of our CSC vaccine via a nanoparticle-based platform.

Collaborations

The investigators in our laboratory work closely with several key collaborators:

  • Dr. Max Wicha, Professor of Internal Medicine and Oncology
  • James Moon, Associate Professor of Biomedical Engineering and Pharmaceutical Sciences
  • Dr. Mark Prince, Chair of the Department of Otolaryngology
  • Gillson Longenbaugh Foundation
  • National Institutes of Health National Cancer Institute
  • MedImmune (now AstraZeneca)
  • Mi-TRAC
  • University of Michigan