Making Headway in Hematologic Cancer Research at UCLA

During the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies in Beverly Hills, California, we spoke with leading oncology experts at the University of California, Los Angeles (UCLA) on the pivotal research being conducted at their institution.

Gary J. Schiller, MD

Gary J. Schiller, MD

Director, Hematologic Malignancies Stem Cell Transplant Unit at the David Geffen School of Medicine, UCLA

“We have about 40 clinical trials [ongoing at UCLA], and at least 15 or more of them are directed against acute myeloid leukemia (AML). We have many different approaches that [we are exploring further]. For example, in patients who are at high risk for relapse, there are therapeutic approaches of T cell add-back in allogeneic transplant that are very interesting.

Again, we’ve used targeted agents in upfront management both with hypomethylating agents and with conventional chemotherapy. Those agents are the closest to getting to the next [regulatory] step, which is submission for consideration of FDA approval.

We have several novel molecules that hit unique targets. I’m not so optimistic about any of those; none of them are really earth-shattering. We desperately need something in the relapsed/refractory setting that targets the kind of disease that we are seeing now in relapse, because it’s very different from years ago. We see TP53-mutated AML, which was something that was nearly unheard of once upon a time, and we see chromosome 3—mutated AML, which is a very aggressive disease. As such, we need something that either broadly hits AML through some discrete antigen or is targeted to these unique mutations. We’re not there yet.”

Joshua P. Sasine, MD, PhD

Joshua B. Sasine, MD, PhD

Director of the CAR T Program, Clinical Instructor of Medicine, Hematologist, and Oncologist, at UCLA

“There are two upcoming studies at UCLA that I would like to highlight. One is [examining] an IL-1 inhibitor used in conjunction with axicabtagene ciloleucel (axi-cel; Yescarta) for diffuse large B-cell lymphoma and mitigating the neurotoxicity. The other study is evaluating a bispecific CAR that recognizes both CD19 and CD20, which we hope will remove one of the escape pathways that the cancer cells can use, namely downregulating or mutating CD19.”

Christopher S. Seet, MD, PhD

Christopher S. Seet, MD, PhD

Assistant Professor, Hematologist, Oncologist, UCLA

“My focus is basic science research. I work on translational approaches to improving T-cell immunotherapy. Currently, there is a lot of excitement in hematologic malignancies in terms of using engineered T cells to target tumors, with CAR T cells being the [interest] of the moment. Obviously, these are all autologous T-cell therapies and they come at a fairly high cost; there is a high logistic difficulty [with] these treatments.

My research looks at the generation of affected T cells in vitro from stem cells. [We want to answer the question], ‘Can we use what we know about stem cell biology to direct the differentiation of hematopoietic stem cells and also pluripotent stem cells to T cells in the laboratory?’ Basically, we start with a self-renewing pluripotent stem cell and we know how to generate T cells in vitro. We have the potential, not only for an unlimited supply of engineered T cells, but also the ability to engineer these cells to be universal donor cells, so off-the-shelf T-cell therapies. That’s the focus of my research in the lab.”

Sarah M. Larson, MD

Sarah M. Larson, MD

Assistant Professor, UCLA

“Right now, I am working with some of our PhD collaborators at UCLA on modifying stem cells for multiple myeloma. [Some of our research] was just published in Cell with the last author being Lili Yang, PhD, of UCLA. We are in the pre-investigational new drug stages of [this work], but it’s very exciting and hopefully we’ll be successful [in our efforts]. We will be using an autologous stem cell transplant platform with modified stem cells to hopefully improve the immune repertoire posttransplant, and then, of course, lead to better outcomes for patients with myeloma.”

John M. Timmerman, MD

John M. Timmerman, MD

Professor of Medicine, UCLA Lymphoma Program, Division of Hematology and Oncology, Department of Medicine, UCLA

“In my research laboratory, we are focused on studying ways of making immunotherapy work better, and we have several new compounds that we’re exploring. One of them is an anti-CD20 [agent] that’s genetically linked to interferon and has several purposes. It has direct antiproliferative effects against lymphoma cells, improved antibody-dependent cellular cytotoxicity, and improved complement-dependent cytotoxicity. In theory, it can increase [the number of] T cells infiltrating into tumors. We’ve seen this happen in some of our early studies.

We’re excited about efforts like this because we’re looking at ways to augment existing immunotherapies. We recently published a paper that looked at sensitizing lymphoma cells to CAR T cells. When we pretreated [patients] with this antibody-interferon[-alpha] fusion protein, we saw higher levels of lymphoma cell [death] and higher levels of cytokine secretion. As such, we’re going to be studying this [approach] in some in vivo models. I believe all of these [efforts] speak to the fact that we’re trying to look for ways to enhance our current immunotherapies, both in terms of antibody mechanisms and T-cell—based mechanisms. To me, that’s where the future lies.”

Herbert A. Eradat, MD

Herbert A. Eradat, MD

Associate Professor, UCLA

“My area of interest at this point is TP53-deficient chronic lymphocytic leukemia (CLL); this still remains an area of great need. When you look at the old prognostic models for CLL with the various chromosomal abnormalities like del(11q), del(17p), and so on, what has fortunately happened with the novel therapies is that none of those molecular features are actually predictive of response. In other words, everybody—including patients with del(11q), del(17p), adverse complex cytogenetics, and so on—responds to the therapy. As such, there is no predictive value there. There is, however, a prognostic value. Most of what I work on has to do with developing novel therapeutic strategies for that subcategory of patients with del(17p) or p53 mutations.”