Unraveling the Complexities of Cellular Immunotherapy and Its Potential to Cure Some Cancers

A Conversation With David G. Maloney, MD, PhD

Get Permission

This past fall, the Fred Hutchinson Cancer Research Center in Seattle opened an all-encompassing 9,222-square foot outpatient cellular immunotherapy clinic, specifically designed to serve patients participating in the center’s novel immunotherapy clinical trials, which mainly focus on chimeric antigen receptor (CAR) T-cell therapy. The Bezos Family Immunotherapy Clinic, named after the family of Amazon CEO Jeff Bezos, who has donated $30 million over the past 8 years to advance the cancer center’s immunotherapy research, will allow Fred Hutchinson researchers to more than double the number of immunotherapy trials it conducts each year—from 5 in 2016 to 14+ this year—and accommodate up to 200 patients. The clinic houses 15 patient care suites, enabling physicians to monitor patients closely for potential toxicities while undergoing treatment, and a research laboratory to test new types of immunotherapy and learn why some patients respond to the therapy and others do not.

In addition to immunotherapy trials for patients with hematologic malignancies, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL), the Bezos Family Immunotherapy Clinic is conducting clinical trials of CAR T-cell therapy for breast and lung cancers. Later this year, the clinic is planning to launch a CAR T-cell trial for patients with multiple myeloma.

The ASCO Post talked with David G. Maloney, MD, PhD, Medical Director of the Bezos Family Immunotherapy Clinic and a member in the Clinical Research Division (CRD) at Fred Hutchinson Cancer Research Center as well as Professor of Medicine in the Division of Oncology at the University of Washington, about how the clinic is advancing research in cellular immunotherapy with the potential to provide durable remissions and possible cures for some patients with cancer.

Treating Solid Tumors: The Next Step

The Bezos Family Immunotherapy Clinic has been open for almost a year. How has the facility improved your ability to conduct cellular immunotherapy research?

We had been excited for several years about the results we were seeing with our CAR T-cell program and became immediately aware we were going to need a larger and more dedicated facility to enable the delivery of cellular immunotherapy to a wide variety of patients with many different cancers on many different treatment protocols. Since the clinic opened this past October, it has given us resources to more than double the number of clinical trials we offer patients. In addition to the eight trials currently opened, we have six trials late in the implentation process, including studies in ALL, CLL, NHL, multiple myeloma, lung cancer, breast cancer, and Merkel cell skin cancer. These trials involve CAR T cells or TCR-transduced T cells alone or in combination with checkpoint inhibitors.

The promising results in CAR T-cell therapy in the hematologic malignancies are what have fueled the excitement in using the therapy in solid tumors.
— David G. Maloney, MD, PhD

Tweet this quote

We have a large dedicated clinical and research staff, including Cameron Turtle, MBBS, PhD [Associate Member, CRD at Fred Hutchinson Cancer Research Center] and Stan Riddell, MD [Member, CRD, and Director of the Immunotherapy Integrated Research Center at Fred Hutchinson Cancer Research Center], with expertise in managing CAR T-cell therapy and its complications, together in one space. That allows us to provide comprehensive care to all our patients on clinical trials.

The promising results in CAR T-cell therapy in the hematologic malignancies are what have fueled the excitement in using the therapy in solid tumors. Translating those responses in leukemia, myeloma, and lymphoma into the more difficult task of treating solid tumors will hopefully be the next step for us.

Are there early indications of how well CAR T-cell therapy works in solid tumors?

We don’t have any data yet on the effectiveness of the therapy in that setting, although it appears to be safe so far. Our CAR T-cell trials in lung and breast cancers are in the early stages, so we do not have information to report yet.

Combining Immunotherapies to Improve Outcomes

What specific areas of research are you engaged in at the Bezos Family Immunotherapy Clinic?

There are several. A key issue in CAR T-cell treatment of lymphomas and leukemias is that it is likely we are going to need to hit multiple targets to completely eradicate the malignancy and potentially render a cure, but we just do not have enough data yet to know for sure. It seems some patients with lymphoma or leukemia can be cured with anti-CD19 CAR T cells; at least some of the patients who underwent the therapy several years ago have not relapsed to date, so this is an important area of research for us.

We are still learning how best to use this therapy and which patients would benefit most. Until we have those answers, we will not completely know its potential.
— David G. Maloney, MD, PhD

Tweet this quote

Generally, for patients with advanced leukemia or lymphoma, we may want to target, for example, both CD19 and CD20 antigens, which would make it more difficult for the malignant cell to escape with an antigen-negative loss variant, but we are not quite ready to test this hypothesis in combination trials. Each of the T-cell receptors has to be tested in clinical trials to determine what its expected efficacy and toxicity are in relation to the dose given.

Once we know that answer, the next question is, Would giving the combination therapy simultaneously or sequentially be more effective than giving the therapy targeting a single antigen? This is an exciting area of research. Another important area of research is learning whether combining CAR T cells with other types of immunotherapies, specifically the checkpoint inhibitor antibodies, will be even more effective in treating these cancers.

We know that when CAR T cells become exposed to the tumor, they express molecules, such as programmed cell death protein 1 (PD-1), which is the target of many of the checkpoint inhibitor antibodies. So combining CAR T-cell therapy with either the PD-1 or programmed cell death ligand 1 (PD-L1) antibody makes a lot of sense. This would have to be done in a careful clinical setting because PD-1 or PD-L1 could also make the CAR T cells expand more rapidly, which might increase toxicity.

There are multiple trials ongoing or in the planning stage combining CAR T cells with checkpoint inhibitor antibodies either following CAR T-cell therapy or in some cases preceding it.

Why Some Patients Respond and Others Do Not

What are you discovering about why some patients respond well to immunotherapy and others do not? And who are the best candidates for this therapy?

Immunotherapy is a big catchword for treatments that stimulate the immune response. In cellular, or CAR T-cell, immunotherapy, there appears to be differences in the responses of patients with CLL, ALL, and lymphoma in terms of how accessible the tumor cells are to T cells. Patients have different degrees of toxicity, in part depending on the dose of T cells as well as their tumor burden.

There are many factors along these lines to consider. Obviously, expression of the target antigen is critical to how well a patient responds to the therapy. If patients have a subset of tumor cells that do not have the target antigen, the treatment will not be effective, because it can only eliminate the cells with the target.

FDA Advisory Committee Supports CTL019 in B-Cell ALL

  • On July 12, the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee voted unanimously in favor of CTL019 (tisagenlecleucel) in the treatment of relapsed or refractory pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL).
  • CTL019 uses autologous peripheral blood T cells that have been reprogrammed with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing malignant and nonmalignant cells.
  • A final decision by the FDA on approval of CTL019 is expected later this year.

Patients’ performance status is also important to consider for eligibility for this treatment. Patients have to be able to withstand the potential for getting fairly sick from cytokine-release syndrome and other toxicities, so it is somewhat important to be in relatively good shape before being exposed to CAR T-cell therapy. Right now, this treatment is only being given in clinical trials, as there are no U.S. Food and Drug Administration (FDA)- approved agents yet. However, that may change soon if the FDA approves tisagenlecleucel (CTL019) in the treatment of pediatric and young adults with ALL. [Editor’s note: In July, an FDA advisory committee unanimously voted to recommend approval of tisagenlecleucel (CTL019). A final decision by the FDA on approval of the therapy is expected later this year.] If the FDA moves forward with approval, it could lead to more patients with leukemia receiving this lifesaving therapy in the coming months. It also affirms the promise of cellular immunotherapy as a treatment for other cancers.

Future of Stem Cell Transplantation

With so many new effective therapies for blood cancers, especially in leukemia, lymphoma, and multiple myeloma, what is the role of stem cell transplantation in these cancers now?

The role of stem cell transplantation in these cancers has not changed at all—yet—and it remains a standard-of-care therapy. However, the question is, Will these new immunotherapies eventually have an impact on stem cell transplantation? Despite all of the novel drugs for the treatment of multiple myeloma, autologous stem cell transplant remains an important part of therapy. Most large phase III clinical trials comparing overall survival rates of novel therapies vs stem cell transplant in patients with myeloma have not been able to eliminate the advantage seen with autologous transplant. But the future of stem cell transplantation remains to be determined.

Clearly, if CAR T-cell therapy, which can be effective, for example in patients with lymphoma who are not eligible for an autologous transplant or who have failed to respond to an autologous transplant, can produce durable complete remission rates in at least one-third to one-half of these patients, it would threaten the continuation of autologous transplant in patients with large cell lymphomas. But in myeloma, we do not have enough data regarding the safety profiles of CAR T-cell therapy or the duration of response to know whether the treatment will threaten the current role of autologous transplant.

A Cure for Cancer?

Some patients with leukemia treated with CAR T-cell therapy several years ago are still in remission. Would you say they cured of their cancer?

I hate to use the word “cure” because it is too spectacular a word. What we can say is that these patients appear to be having durable remissions in some percentage of the cases, but not in every case. There are patients who relapse with tumors that no longer express CD19, for example, which is a failure of the therapy but not a failure of the CAR T cells. It just means the tumor doesn’t have to express the target antigen, and the CAR T cell could not do any better job at killing the tumor in that case.

It may be the target selection was not correct, or we need to treat patients earlier in their disease before they have a high risk of mutations. We still have to be cautious when treating patients with this therapy and need to monitor them long term to determine the relapse pattern.

We are still learning how best to use this therapy and which patients would benefit most. Until we have those answers, we will not completely know its potential. ■

DISCLOSURE: Dr. Maloney has received institutional research funding from Juno Therapeutics for protocols on which he is primary investigator. He is also on the advisory boards of Kite Pharma and Celgene.