The Direction of Immunotherapy Over the Next Decade 

A Conversation With David L. Porter, MD


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The use of immunotherapy to target malignant cells in a variety of cancers—especially the PD-1 inhibitors lambrolizumab and nivolumab in the treatment of metastatic melanoma and the anti–PD-L1 agent MPDL3280A in the treatment of melanoma and lung, kidney, colorectal, and gastric cancers—made headlines at ASCO’s Annual Meeting in June. The success of these drugs in early-phase clinical trials builds on the momentum created by previous studies testing other therapies that use the body’s immune system to kill cancer cells.

At the 2012 Annual Meeting of the American Society of Hematology, David L. Porter, MD, and colleagues at the University of Pennsylvania, presented their updated findings of a pilot study in 12 patients with leukemia, including 10 adults with advanced chronic lymphocytic leukemia (CLL) and two children with acute lymphoblastic leukemia (ALL) who had been treated with genetically engineered versions of their own T cells. Their findings showed that nine patients responded and three patients had no response to the therapy.

Since then, a total of 24 adults with CLL and 10 children with ALL have been treated with gene-transfer therapy. In the longest follow-up to date, the first CLL patients treated with the therapy have remained in remission for 3 years, and the first child with ALL treated with the therapy has had a sustained remission of more than 1 year.

The treatment, known as CTL019 (previously known as CART19), was pioneered by the University of Pennsylvania researchers and involves isolating a patient’s own T cells, genetically modifying them with a lentiviral vector expressing an antibody-like protein called chimeric antigen receptor (CAR). The cells are designed to attack the protein CD19 expressed on the surface of certain B cells. The reengineered cells are expanded and then injected back into the patient.

The ASCO Post talked with Dr. Porter, Director of Blood and Marrow Transplantation and Professor of Medicine at the Abramson Cancer Center of the University of Pennsylvania, about the progress being made in immune therapy approaches, especially in cell-based therapies, and how immunotherapy may be the answer to curing cancer in the future.

Dramatic Progress

Please talk about how far research has come in understanding how to harness the body’s immune system to fight cancer.

There has been dramatic progress over the past decade in understanding how to use the immune system. We have known for more than 50 years that the human immune system has the potential to be a very powerful anticancer therapy. Part of the rationale for doing bone marrow transplantations was to give the patient a new immune system, which could help fight the patient’s cancer, and I think that’s where so much interest in cellular immunotherapy originated.

Over the years it has been possible to develop targeted therapy in the form of antibodies, and now in the form of cell-based therapy. There has also been tremendous progress in understanding very complicated interactions with the immune system. One can now manipulate and downregulate inhibitory signals or immune suppressors like regulatory T-cells. Researchers have also developed efficient methods that allow us to stimulate and grow immune effector cells for clinical use.

From a cell-based therapy standpoint, one big advance have been in the ability to grow immune cells in the laboratory in numbers large enough so they could be used therapeutically. Now, particularly with some of the work that we have been doing to grow specific immune-cell populations, we can confer novel specificity to the T cells and make the immune function much more targeted and specific, and eliminate some of the off-target toxicities that you often see with nonspecific immunotherapy.

Looking Ahead

What advances in cell-based therapy do you see happening over the next decade?

We need a better understanding of the T-cell and other immune-cell populations that are needed to kill cancer cells. Our knowledge of the interactions among immune effector cells is increasingly complex, but we need an even better understanding of how these cells function and interact to maximize the response to cellular therapy.

I think the biggest limitation that has to be overcome is the identification of the appropriate targets on cancer cells. We have been treating ALL and CLL by targeting CD19, which is an ideal cancer target.

The problem with many cancers is that they are too close to self and there aren’t easily identifiable target antigens that allow you to apply immune therapy without off-target toxicity.

 

How will you be able to overcome that problem?

I sincerely believe that over the next 5 to 10 years, some of the biggest advances will come from identifying new targets for various kinds of cancers and then applying vaccine therapy, antibody therapy, and cellular therapy against these specific targets. This will be done through extensive studies of cancer cell biology, DNA sequencing, and other techniques that will allow this type of immunotherapy to become increasingly personalized to a patient’s specific tumor and the tumor’s specific targets. I believe that it will be possible to accomplish this for many, if not most, cancers over the next decade.

Immunotherapy vs Chemotherapy

Will immunotherapy render conventional types of chemotherapy obsolete?

It’s going to be a long time before chemotherapy is obsolete. Some chemotherapy may actually have a role concurrently with immunotherapy and may function to modulate the immune interactions. There may be instances where we use multimodality therapy, including chemotherapy, radiation therapy, and immunotherapy.

The biggest downside to chemotherapy is its complete lack of specificity. If you could use less and use it more judiciously, or use it to modulate other therapy, presumably the toxicity will be less.

Curing Cancer

Could immunotherapy be the answer to curing some cancers?

Immunotherapy can already cure some cancers. Going back to the example of bone marrow transplantation, there are circumstances when patients with leukemia or lymphoma relapse after allogeneic transplant and can be cured with infusions of normal T cells from their original transplant donor (donor lymphocyte infusion).

Immune therapies are the new frontier in cancer therapy, and the field is in its infancy. Although there are not many examples of immunotherapy curing cancer yet, I anticipate that the application of immunotherapy in the treatment of cancer will grow dramatically over the next decade.

CAR Technology

Your current research is focused on using viral transfection to genetically modify T cells to express a chimeric antigen receptor (CAR) in patients with CLL and ALL. Are you planning studies in other hematologic cancers using CAR?

We hope to be able to expand this therapy to patients with non-Hodgkin lymphoma very soon, but we believe that this approach is applicable to other targets as well. Our initial work is focused very heavily on CD19 and on expanding CD19 targets, and then we hope to use similar chimeric antigen receptor technology to target other tumor types once targets can be identified.

For example, we are hoping to open a study with multiple myeloma patients over the next few months. We are thinking very hard about how best to target myeloma cells and how we can apply similar chimeric antigen receptor technology to patients in the setting of stem cell transplant. In myeloma, we think the best strategy may be to prevent patients from relapsing, so we are initially hoping to target patients who are at high-risk for relapse or who have minimal residual disease, and would administer chimeric antigen receptor therapy early after a transplant.

Wider Applicability

Is cellular-based immunotherapy applicable to solid tumor cancers as well as blood cancers?

The hope is that immunotherapy will be effective for solid tumors as well. Studies using targeted immune therapy in patients with breast and ovarian cancer are just getting underway, and other cell-based therapy trials are targeting brain tumors, sarcomas, and other cancers. We will know in several years whether we can target solid tumors effectively. But, again, the problem is identifying those unique targets.

 

Not all the patients in your study responded to this treatment. Is there an ideal candidate for this type of therapy?

We don’t know the answer to that yet. We have treated about 24 people, and we have not yet been able to identify factors that predict who may or may not respond to the therapy, but we are working very hard to do that.

Clinical Trials

How will clinical trials need to be designed over the next decade to effectively test this type of therapy?

Trials need to be designed so that we can initially test not just the level of activity of immunotherapy but its safety as well. There are unique issues with the long-term safety of immune therapy, particularly with gene therapy. Ultimately, it’s going to be important to develop randomized clinical studies to show that immunotherapy may be superior to other treatment modalities. But right now we are still in the early phases of trying to show that there is a role for these types of treatments.

At the University of Pennsylvania, we plan to open a Center for Advanced Cellular Therapies, where we can take immunotherapy from the basic research of target identification, vector development, and cell manufacturing all the way through the clinical trial process. ■

Disclosure: Dr. Porter receives research support from Novartis and has IP interests on technology licensed to Novartis. Conflict of interest is managed in accordance with oversight and policies of the University of Pennsylvania. Dr. Porter’s spouse is employed by Genentech.



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