Aiming for Immunity: New Therapies in Sights

Even before the FDA approved ipilimumab in March, the field of cancer immunotherapy was a lively area of scientific inquiry. Now, experts expect the success of the melanoma drug Yervoy to further draw research attention toward developing ways of helping the human body’s innate defenses fight tumors.

In fact, the breadth and complexity of immunotherapeutic approaches are unfolding as the possibilities mushroom.

The 2011 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois, in June provided a plethora of new research, with reports on a variety of vaccines, combinations with standard therapies, and novel strategies to reduce the dysfunction of the immune system.

“We’re going to have an explosion of possible combinations,” Thomas F. Gajewski, MD, PhD, president of the Society for Immunotherapy of Cancer (SITC), said in an interview with OncLive. “It’s going to be a challenge to prioritize those so that the most effective candidates get tested first.

Thomas F. Gajewski, MD, PhD

“At the same time, that makes it exciting,” added Gajewski, a professor in the departments of Pathology and Medicine, Section of Hematology/Oncology at the University of Chicago Medical Center. “Now that things are starting to click, there’s going to be a lot of work.”

Indeed, Tyler J. Curiel, MD, MPH, a professor of Medicine at the University of Texas Health Science Center in San Antonio, said researchers have much work to do to understand how the immune system breakdown that cancer cells induce can be overcome.

“Right now, we don’t really have a very good understanding of what are the specific immune factors generated by active interventions that would lead to a positive outcome in cancer,” he said during a presentation at the ASCO congress entitled “Progress in Tumor Immunotherapy.”

Tyler J. Curiel, MD, MPH

There are many big questions, he said, starting with defining the critical dysfunctional pathways, cells, and factors. “What are the optimal means to intervene? Who are the ideal patients? How should these strategies be combined?” he asked.

Such questions already are making immunotherapy one of the most active areas of cancer research, with more than 80 possibilities in various stages of discovery, according to the Oncology Business Review, an industry publication.

“Immunotherapy is going to become one of the key treatment modalities in cancer over the coming years,” said Axel Hoos, MD, PhD, medical lead for Yervoy at Bristol-Myers Squibb and co-chair of the executive committee of the Cancer Immunotherapy Consortium, in an OncLive interview.

New Approach Creates Excitement

The ASCO congress was a moment in the spotlight for ipilimumab, not only because it demonstrated the ability to prolong survival in a disease for which no new drug had been approved for more than a decade, but also because of its mechanism of action.

Axel Hoos, MD, PhD

Ipilimumab, which is administered intravenously, is a humanized monoclonal antibody that blocks the cytotoxic T-lymphocyte antigen 4 (CTLA-4) molecule from inhibiting antibody response to cancer cells, thus allowing the T cells to proliferate and fend off alien antigens.

The drug takes the brakes off the immune system, said James P. Allison, PhD, chairman of the Immunology Program at the Memorial Sloan-Kettering Cancer Center in New York City, whose discoveries led to the development of ipilimumab.

Related: Independence and Tenacity Anchor Immunology Pioneer: A Closer Look at James P. Allison, PhD

The immune cosignaling blockade approach that ipilimumab employs is among the emerging areas of inquiry. Because ipilimumab treats the tumor and not the specific disease state, the drug has the potential for use against many other cancer types.

“It has broken new ground for cancer immunotherapy in general,” and is a first-in-class agent because of the way it enhances T-cell activation, Hoos said.

As a result of the drug’s success, “we’re beginning to see more broad acceptance of immunotherapies in the oncology community at large, and it certainly defines immunotherapy as a treatment modality for cancer,” Hoos noted. “It makes it more likely there will be further investigations that are successful.”

Illustration depicts a spacefill model of an antibody. The use of monoclonal antibodies in cancer immunotherapy has been highly successful.

Researchers Battled Skepticism

If success breeds success for immunotherapy approaches this time around, past disappointments have made researchers feel as though they were fighting for acceptance of their theories.

The cycle has been one of soaring hopes dashed by clinical realities. In the 1970s, developing monoclonal antibodies (mAbs) generated so much excitement that they were touted as “magic bullets,” according to a report from the Cancer Research Institute and MD Becker Partners LLC (Report).

Disappointment set in when it took until 1997 for the fi rst drug in the class, rituximab (Rituxan), to gain approval. Now, the passive immunotherapy drugs are “one of the most successful therapeutic classes,” the report notes.

Likewise, active immunotherapies at first proved disappointing.

“In part, those disappointments have come from some of the vaccine approaches that were promising in the early going and did not pan out in clinical trials,” said Gajewski.

He said, though, that when bright prospects dimmed, “it forced researchers to try and fi gure out the mechanisms,” and that has in turn helped identify barriers to immune functions, which are now being targeted.

At its heart, immunotherapy is defined as biologic therapy that uses parts of the immune system to fight cancer, with therapy approaches broadly defined as active, passive, and targeted immunotherapies, according to the American Cancer Society.

FDA-Approved Cancer Immunotherapies

Monoclonal Antibodies

Disease State

Approval

Rituximab (Rituxan)

Non-Hodgkin lymphoma (NHL)

Chronic lymphocytic leukemia (CLL)

1997

2010

Trastuzumab (Herceptin)

Breast cancer

Stomach cancer

1998

2010

Gemtuzumab

ozogamicin (Mylotarg)

Acute myelogenous leukemia

2000†

Alemtuzumab (Campath)

CLL

2001

Ibritumomab tiuxetan* (Zevalin)

NHL

2002

Tositumomab* (Bexxar)

NHL

2003

Cetuximab (Erbitux)

Colorectal cancer

Head & neck cancers

2004

2006

Bevacizumab (Avastin)

Colorectal cancer

Non-small cell lung cancer

Breast cancer

Glioblastoma

Renal cell carcinoma (RCC)

2004

2006

2008

2009

2009

Panitumumab (Vectibix)

Colorectal cancer

2006

Ofatumumab (Arzerra)

CLL

2009

Denosumab (Xgeva)

Cancer spread to bone

2010

Ipilimumab (Yervoy)

Melanoma

2011

Vaccines‡

Sipuleucel-T (Provenge)

Prostate cancer

2010

Cytokines/Proteins

Interleukin-2 (IL-2)

(aldesleukin, Proleukin)

(denileukin diftitox, Ontak)

RCC, melanoma

Cutaneous T-cell lymphoma

1992, 1998

1999

Interferon alfa-2b (Intron A)

Hairy cell leukemia

Melanoma

Follicular lymphoma

1986

1995

1997

Other Adjuvants

Bacille Calmette-Guérin(TICE BCG)

Bladder cancer

1998

Immunomodulating Agents

Thalidomide (Thalomid)

Lenalidomide (Revlimid)

Multiple myeloma (MM)

MM

1998**

2005

Sources: American Cancer Society, Drugs @ FDA database, prescribing information for individual drugs.

* Conjugated monoclonal antibodies that are radiolabeled

† Approval withdrawn as of October 15, 2010; this drug is only available for use within a clinical trial

Indication under FDA review

‡ Human papillomavirus and hepatitis B vaccines target viruses that can cause cancer and are not considered immunotherapy vaccines

** Initial FDA approval for treating erythema nodosum leprosum

While many forms of immunotherapy are under investigation, the society said FDA-approved options include 12 mAbs, 2 cytokines/proteins, and 2 immunomodulating agents.

Although several preventive vaccines that target cancer-causing viruses have been approved in recent years, sipuleucel-T (Provenge) is the only “true cancer vaccine” because it uses cancer cells to stimulate the body’s immune response, according to the society. The vaccine, which the FDA approved in April 2010, is custom-manufactured for each patient using dendritic cells harvested through

Searching for a New Paradigm

While sipuleucel-T marks a milestone in cancer therapy, some researchers are looking toward other strategies for future immunotherapies. Curiel said the vaccine’s approach is part of an “old paradigm” built upon boosting good elements such as antigens or killer cells to improve responses.

Curiel said that paradigm has 3 shortcomings: the lack of tumor rejection is not just because there are insufficient beneficial immune elements; boosting the numbers of potentially beneficial immune elements has led only to modest successes; and boosting functions of potentially beneficial immune elements has led to only modest successes.

He said a new paradigm is needed that recognizes that “the tumor itself is contributing to immune dysfunction in the cancer.” Strategies under investigation include reducing regulatory T cells, reducing inhibitory factors, myeloablating dysfunctional immune cells, and immune cosignaling blockade.

“In this new paradigm, if you can turn off the dysfunction, you get rid of these regulatory T cells, you get rid of these dysfunctional antigen-presenting cells, and now you turn on the function of the cytotoxic T cells, antigen-presenting cells can work better, and perhaps putting these 2 concepts together—turning off the dysfunction then coming in with an active intervention—is what we need,” Curiel said.

In addition, Curiel said, researchers are exploring strategies to overcome immunoediting, whereby tumors mutate in order to evade natural and therapeutic attacks.

“It’s like today’s army’s marching off to war with the last war’s boots,” he said. “Your immune system is sitting there waiting to recognize a tumor that has mutated, and it’s not what it used to be.”

As researchers delve into the challenges, one thing seems certain: The studies will be wide-ranging.

“We have moved away from the classical notion that only a few, restricted types of tumors are candidates for immunotherapy and [are] immunogenic, but rather perhaps the majority of solid tumors are targets for immunotherapy,” observed George Coukos, MD, PhD, professor of Reproductive Biology in the Department of Obstetrics and Gynecology at the University of Pennsylvania School of Medicine in Philadelphia, a discussant at ASCO.