Robert Jenq, MD

I am interested in developing strategies that reduce malignant relapse after hematopoietic stem cell transplantation (HSCT). To this goal, I have studied therapies that modulate the ability of the immune system to eradicate residual cancer cells, using mouse models of HSCT.

There are ample preclinical and clinical evidence for profound immune responses mediated by allogeneic HSCT against malignancy, contributing to its curative potential. My work is based on the hypothesis that by harnessing the immune system in a targeted way, rates of malignant relapse can safely be further reduced. Means by which the immune system can be targeted against residual malignancy include tumor vaccines, monoclonal antibodies, and cellular therapies.

Current strategies:

Keratinocyte growth factor (KGF). We have studied the combination of DNA tumor vaccines and KGF in mouse HSCT models in a collaborative project between the laboratories of Marcel van den Brink and Alan Houghton. We found that KGF markedly enhances the efficacy of post-HSCT DNA tumor vaccination. This work was recently published in Blood.

WT1 DNA vaccine. We have developed a DNA vaccine targeting the tumor antigen WT1, which is overexpressed in the majority of leukemias, as well as many solid tumors. Preliminary experiments have demonstrated that this vaccine elicits T cell immune responses against WT1-expressing leukemia cell lines as well as WT1 peptide epitopes. We are now evaluating the efficacy of this vaccine in tumor-bearing mice, as well as after HSCT and combined with KGF.

Reprogramming tumor regulatory T cells (Tregs). In many tumors, the majority of infiltrating T cells are suppressive and carry the marker/transcription factor Foxp3. We have developed retroviral vectors that can knock down expression of Foxp3 and at the same time overexpress Tbet. By reducing Foxp3 levels and forcing expression of the Th1 transcription factor, Tbet, we hope to reprogram these Tregs into helping augment anti-tumor responses in a tumor-specific way. The converse approach, converting non-Tregs into Tregs with forced expression of Foxp3, has proven to be an effective treatment for autoimmunity in preclinical models. This approach would thus develop a novel form of cellular therapy, as well provide a means of understanding which tumor antigens are recognized by tumor Tregs.

Evaluating the basis of anti-prostate cancer immune responses of donor female T cells. This project capitalizes on the observation that T cells from individuals that have not been tolerized against tumor antigens have increased potential for anti-tumor activity. In collaboration with James Allison's laboratory, we have found that an HSCT from female into male mice produces significant anti-prostate cancer immunity. We have demonstrated that T cells from prepubescent male mice initially have some anti-prostate cancer potential, which is then reduced following puberty. Female T cells are capable of recognizing Y-chromosome antigens expressed by the prostate cancer cells, and we are currently evaluating additional responses of female T cells against androgen-regulated antigens. Interestingly, in our mouse models we have found significant anti-tumor responses in the absence of lethal graft-versus-host disease.