High Points and Hurdles: Immunotherapy Moves Forward

Illustration depicts T lymphocytes attacking a migrating cancer cell. Novel ways to improve the ability of T lymphocytes to enhance immune response are under study.

At this time last year, immunotherapy was in the limelight. Within a span of less than 12 months, the FDA had approved the first anticancer therapeutic vaccine and an antibody with a unique mechanism of action. Advocates of cancer-fighting immune strategies felt vindicated after facing skepticism and disappointment.

Today, immunotherapy is maintaining its momentum in clinical development programs, with explorations under way in many tumor types, including breast and lung cancers previously considered poor candidates for such modalities.

More than a dozen active immunotherapies are in late-stage development (Table 1 Below). And, an early-phase study into an immunotherapy agent targeting the programmed death-1 (PD-1) pathway in three different tumor types emerged as one of the most noteworthy abstracts at the American Society of Clinical Oncology (ASCO) annual meeting in June.¹

At the same time, significant challenges remain in translating research discoveries into clinical use and in the marketplace, where immunotherapy has sometimes struggled to establish solid financial footing.

OncologyLive interviewed several experts on the front lines of the immunotherapy field. Here are their thoughts:

Mary L. (Nora) Disis, MD

Professor, Medicine and Oncology, University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA

Mary L. Disis, MD, is a chief co-investigator of the Cancer Immunotherapy Trials Network (CITN), which links researchers at 27 institutions with the intention of creating a pipeline of agents that can move into advanced trials. The National Cancer Institute launched the network in April 2011, designating the Fred Hutchinson Cancer Research Center as its headquarters.

Disis said the rationale for establishing the CITN was “the explosion of new agents that are being developed for the immune system,” particularly after the FDA approved sipuleucel-T (Provenge) for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer in April 2010 and ipilimumab (Yervoy) for unresectable and metastatic melanoma in March 2011.

“Seeing the approval of immune therapy treatments really working in patients with very advanced-stage disease, where you would expect the immune system wouldn’t be so effective, has spurred a desire to rapidly test and bring forward novel reagents across different tumors, not just melanoma or prostate cancer, that will really make a difference in the lives of patients with both advanced-stage disease and earlier-stage disease,” said Disis.

The CITN members plan to work as a unit to design trials and investigate biomarkers.

Table 1. Novel Active Immunotherapies in Late-Stage Development

Agent

Tumor Type

Description

Sponsors/Partners

Status

AGS-003

(Arcelis)

Newly diagnosed, metastatic renal cell carcinoma

Autologous dendritic cells loaded with patient's messenger RNA

Argos Therapeutics

Phase III ADAPT trial to start mid-2012; FDA Fast Track designation

Algenpantucel-T

(HyperAcute)

Stage I/II pancreatic adenocarcinoma after surgical resection

2 separate allogenic pancreatic cancer cell lines engineered to express a-Ga

NewLink Genetics Corporation

Phase III under way; FDA Fast Track designation

Allovectin-7

First-line treatment for stage III/IV melanoma

Plasmid/lipid-based, encoding DNA sequences for HLA-B7 and β2 microglobulin to form an MHC class I complex

Vical/AnGes MC

Phase III trial in final stages of patient follow-up; FDA Fast Track designation

BiovaxID

Indolent follicular non-Hodgkin lymphoma

Hybridoma-derived idiotype vaccine made from patient's tumor cells

Biovest International/ National Cancer Institute

Phase III trial completed; FDA filing planned

IMA901

Advanced/metastatic renal cell carcinoma

Combination of multiple tumor-associated peptides

immatics biotechnologies GmbH

Phase III trial under way

Lucanix

Stage IIIB/IV NSCLC after 0-5 prior chemotherapy treatments

Four NSCLC cell lines gene-modified to block the secretion of TGF-β

NovaRx Corporation

Phase III trial under way; FDA Fast Track designation

MAGE-A3

Melanoma, NSCLC

Recombinant antigen-specific cancer immunotherapeutic

GlaxoSmithKline

Phase III trials under way

Multikine

Advanced primary squamous cell carcinoma of the oral cavity/soft palate

Mixture of cytokines, including interleukins, interferons, chemokines, and colony-stimulating factors

CEL-SCI Corporation/Teva Pharmaceuticals Industries/ Orient Europharma

Phase III trial under way

NeuVax

Early-stage, node-positive breast cancer with low-to-intermediate HER2 expression

Peptide derived from HER2 combined with GM-CSF

Galena Biopharma

Phase III PRESENT trial under way

PROSTVAC

Asymptomatic or minimally symptomatic castration-resistant prostate cancer

Sequentially dosed combination of Vaccinia and Fowlpox poxviruses that encode prostate-specific antigen plus three immune-enhancing costimulatory molecules

Bavarian Nordic A/S

Phase III PROSPECT trial under way

Rindopepimut

(CDX-110)

Surgically resected, EGFRvIII-positive glioblastoma

Consists of EGFRvIII antigen chemically conjugated to the protein keyhole limpet hemocyanin

Celldex Therapeutics

Phase III ACT IV Study under way

Stimuvax

Unresectable stage III NSCLC in patients with response or stable disease after ≥2 cycles of chemo-radiotherapy

25-amino acid sequence of the cancer-associated marker MUC-1 in a liposomal formulation

Oncothyreon/Merck KGaA

Phase III START trial under way

Talimogene laherparepvec

(formerly OncoVex^GM-CSF)

Unresectable stage IIIB/IIIC/IV melanoma

Herpes simplex virus type 1 engineered to express GM-CSF

Amgen

Phase III study under way

TG4010

(MVA-MUC-IL2)

Stage IV NSCLC

Modified Vaccinia virus vector expressing the MUC1 antigen and interleukin-2

Transgene/Novartis

Phase IIB/III trial under way

EGFRvIII indicates epidermal growth factor receptor variant III; GM-CSF, granulocyte macrophage colony-stimulating factor; NSCLC, non-small cell lung cancer.

Sources

Cancer Research Institute and MD Becker Partners. Cancer immunotherapy: a roundtable discussion. MD Becker website. http://mdbpartners.com/?s=roundtable. Published June 30, 2011. Accessed June 6, 2012. Securities and Exchange Commission filings, annual reports, press releases for individual companies.

ClinicalTrials.gov website.

In her own work, Disis has been investigating potential immunotherapies in breast cancer for 20 years. In the past, breast tumors typically were not considered immunogenic, but research advances indicate the opposite. She believes that the immune system can be stimulated not only to treat breast cancer but also to prevent relapse.

“There have been several immunologic signatures associated with breast cancer that predict survival,” said Disis. “These signatures are related to infiltrating CD8 T-cells, which are killer T-cells. They’re kind of the main arm of the immune system in being able to eradicate cancer, predicting patients who do well overall versus patients who do worse with disease.

Since the immune system is a series of checks and balances, one avenue of exploration is to train the body to defend itself against tumor cells. In addition, improved understanding about how chemotherapies work on the molecular level and about the stimulatory action of established agents such as trastuzumab (Herceptin) may lead to other immune approahces.

“With what we’re learning about standard treatments in breast cancer, along with multiple different types of immune-based therapies that are being developed even in other diseases, I’m confident that in the next two to three years, we’ll see some combination immunotherapies moving forward for breast cancer treatment,” said Disis.

Disis also has been working on a vaccine that targets HER2/neu, the protein overexpressed in at least 25% of all breast cancers. She said several pharmaceutical companies are moving toward phase III trials with HER2/neu vaccines.

Such vaccines could help prevent relapse in patients who have been effectively treated for breast cancer.

“The immune system is ideally poised to particularly fill this niche,” she said. “With vaccination, you might be able to immunize like you would against a foreign pathogen, generate an immune response that was long-lasting, that stuck with the patient after vaccination, so that when a year or two years, five years, 10 years later the disease showed its face again, the immune system would already be primed to go where antigen was being expressed and to kill the cancer before you even knew that you relapsed.”

Thomas F. Gajewski, MD, PhD

Professor, Medicine, The University of Chicago Medicine, Center for Advanced Medicine, Chicago, IL

Thomas F. Gajewski, MD, PhD, is president of the Society for Immunotherapy of Cancer (SITC), a Milwaukee, Wisconsin-based organization whose members include some of the nation’s most prominent immunotherapy researchers. He has led and participated in clinical investigations of several immunotherapy strategies involving melanoma, including research into ipilimumab and PD-1.

He feels that immunotherapy has overcome any lingering skepticism in scientific and financial circles.

“The successes with the two recently approved therapies have established a foundation that is maintaining enthusiasm,” Gajewski said in an email interview. “There are more companies forming immunotherapy units and multiple new agents being tested in the clinic.”

Specifically, Gajewski pointed to research presented this year at ASCO concerning BMS-936558, which uses a checkpoint blockade strategy similar to that employed by ipilimumab.¹

The investigational agent, which Bristol-Myers Squibb is developing, is a monoclonal antibody that targets PD1 proteins, which are expressed on the surface of tumor-fighting T cells but which will turn off the body’s immune system if they join with PD ligand 1 (PD-L1). By attacking PD1, BMS-936558 takes the brakes off the immune system.

“PD-1 is a cousin of CTLA-4, the target of ipilimumab, and is another inhibitory receptor on activated T cells,” said Gajewski. “The response rate with anti- PD-1 antibodies is at least 30% in melanoma, and there have been responders in lung cancer and kidney cancer so far. So the excitement is continuing.”

At the same time, there are obstacles that have presented difficulties in furthering cancer immunotherapies, and the SITC is working with societies from Europe, Japan, China, and North America to identify problems and discuss ways to overcome them.

Table 2. Nine Hurdles Facing Immunotherapy^²

1

2

3

4

Limited availability of reagents for combination

immunotherapy studies

5

6

7

Conventional response criteria may not reflect the patterns of response to immunotherapies

8

9

Need to enhance exchange of information critical

to advancing the field

Limitations of preclinical animal models Delayed institutional, administrative, and regulatory approval Complexity of cancer, tumor heterogeneity, and immune escape Limited funds available to translate science into patients Lack of definitive biomarkers of immune response Paucity of translational teams of scientists and clinicians

In December, Gajewski and others defined nine hurdles to the development of immunotherapies in the Journal of Translational Medicine. (Table 2). 2 The authors noted that despite the promise of immunotherapy to produce responses in patients with even the most advanced cancers “the translation of these discoveries from ‘the bench to the bedside’ has been painfully slow.”

One hurdle that leading researchers frequently discuss involves the measures used to evaluate whether an immunotherapy treatment is working in a particular patient. For some patients, tumors may grow before they start to shrink.

Investigators have proposed that new criteria be developed. They cite four patterns of response to immunotherapy that have been associated with favorable outcomes: ²

• Shrinkage in baseline lesions, without new lesions
• Durable stable disease (in some patients followed by a slow, steady decline in tumor burden)
• Response after an increase in total tumor burden
• Response in the presence of new lesions

In addition, the SITC and its research partners are developing a standard for classifying the immune status of a tumor.³ The immunoscore would be assessed at the time of diagnosis, along with such established criteria as tumor burden, presence of cancer cells in draining and regional lymph nodes, and evidence of metastases.

The immunoscore would be based on the tumor microenvironment. “Global analysis of the tumor microeinvironment showed that the immune contexture, ie, the nature, functional orientation, density, and location of adaptive immune cells within distinct tumor regions influence the risk of relapse,” the authors said.

While such questions are debated, oncology specialists face other complexities in prescribing immunotherapies. Speaking from his vantage point concerning melanoma, Gajewski noted the impact of cost factors in adopting the therapy.

Ipilimumab is administered intravenously, with a complete course of treatment consisting of four infusions during a three-month period at a cost of $30,000 per infusion, or $120,000 for the series, Bristol-Myers Squibb officials have said.

“I know that many community oncologists are using ipilimumab, but some are not, mainly because of the cost.” Gajewski said in his email. “We are still getting some referrals because small practices can have difficulty paying up front for this expensive drug. So my own view is that the cost of these new biologic agents will have to come down eventually, also to make them more available worldwide.”

Michael D. Becker

Founder Senior Partner MD Becker Partners LLC Washington Crossing, PA

Over the years, Michael D. Becker has been on several sides of oncology drug development as a financial analyst, investor, and biotechnology entrepreneur, including a stint as president and chief executive officer of the former Cytogen Corporation and VioQuest Pharmaceuticals, Inc. These days, he focuses on cancer immunotherapy at the boutique consulting firm he operates.

Although many companies are developing immunotherapies, Becker said access to investment capital remains dicey for smaller biopharmaceutical companies, particularly because of the rocky road that Dendreon, the Seattle, Washington-based company that developed Provenge, has been traveling.

“There still is a lot of fragility in the marketplace as it relates to cancer immunotherapy,” he said. “Dendreon’s Provenge was a watershed event, the big moment that everybody in cancer immunotherapy was waiting for—to get a product to show clinical benefit and get ultimately approved by the FDA after a lot of failures.

“The fact that we finally had one that got across the finish line was very important, but I think people maybe overestimated just how that was going to change negative perceptions about prior clinical failures and even adoption in the marketplace, and really kind of placed too much importance on that singular product instead of looking at all the recent advancements that have been occurring in the industry,” he said.

Unlike ipilimumab, which is an intravenously administered therapeutic that advances accepted monocolonal antibody strategies, sipuleucel-T is a first-in-class autologous vaccine that has pioneered the use of dendritic cells amid evolving understanding of how immunotherapies work in patients.

Its adoption got off to a slower start than Dendreon executives had anticipated, and there were questions about how oncologists would be reimbursed for the estimated $93,000 cost of a full treatment regimen. In recent months, the company has settled reimbursement questions, trimmed its workforce, and installed new leadership.

In May, Dendreon executives said during a conference call with analysts that Provenge has been gaining acceptance among community oncologists and urologists, with a growing number prescribing the therapy for their patients.

The company reported that revenue from Provenge was approximately $82 million during the first three months of 2012, representing a 6.5% increase over the prior quarter, and that the number of locations where the vaccine was administered to patients had risen. Previously, Dendreon reported that Provenge generated $261.5 million in revenue from the time of the FDA approval in April 2010 through the end of 2011.⁴

While tens of millions in sales might be a success story for many products, the costs of producing the vaccine have proved daunting and Dendreon continues to lose money. Sipuleucel-T is custom-made from antigenpresenting cells harvested from the patient through the process of leukapheresis, then cultured to activate immunogenicity, and infused into the patient. The treatment course consists of three intravenous infusions.

Dendreon executives said in the conference call that they are working to reduce the costs of producing Provenge and that they anticipate further improvements as the year unfolds.

Meanwhile, the company’s experiences affect the sector.

“Every time Dendreon sneezed, the rest of the cancer immunotherapy field caught a cold,” said Becker. “If Dendreon is having a good day, many of the other cancer immunotherapy company stocks also go up, and conversely, they go down when Dendreon goes down.”

Although he said investors are starting to differentiate between immunotherapy companies, they are waiting for more evidence that novel immunotherapies are viable clinically and commercially. (Becker’s clients include Bavarian Nordic, which is developing the PROSTVAC vaccine that would, if approved, compete with Provenge).

“We’ve seen, through our interactions with investors, that many of them are saying, ‘You know what, I’m holding off until I see at least one more success story in the field before I put money to work in cancer immunotherapy,’” said Becker. “Investors are just saying, ‘Give me just one more reason to be hopeful that there’s value in cancer immunotherapy.’”

Becker believes that success story could be a positive later-stage clinical trial, a major pharmaceutical company acquiring an immunotherapy license from a developmental company, a notable merger or acquisition in the field, or improved sales of Provenge.

He does, however, feel that advances in immunotherapy— with more products making it to patients— are inevitable.

Leonard G. Gomella, MD

The Bernard W. Godwin Jr Professor of Prostate Cancer, Chairman, Department of Urology, Director, Clinical Affairs, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA

Leonard G. Gomella, MD, has conducted extensive research into the use of immunotherapy in patients with prostate cancer, particularly with sipuleucel-T, for which he was among the principal investigators in the trial that led to its approval.

Earlier this year, Gomella presented an updated analysis of clinical trial data for sipuleucel-T, indicating that the survival advantage for patients treated with the vaccine likely was far greater than the 4.1-month benefit reported in the pivotal trial that led to its approval. The advantage increased because so many patients in the control arm responded after crossing over to a cryopreserved form of the vaccine.⁵

Gomella remains enthusiastic not only about the future prospects for sipuleucel-T but also about immune- based strategies to treat prostate cancer.

“We did come over a hurdle about 10 years ago in prostate cancer, realizing from a molecular standpoint and from a proteomic and immunologic standpoint that you could stimulate the immune system to recognize prostate cells or turn on the immune system in order to fight advanced prostate cancer,” said Gomella.

During the 5th Annual Interdisciplinary Prostate Cancer Congress (IPCC) in New York City in March, Gomella outlined four distinct approaches to immunotherapy that show promise for clinical advancement in prostate cancer. These are:

• Sipuleucel-T—A vaccine using dendritic cells through the leukapheresis process
• PROSTVAC—A vaccine that employs pox viral vectors to stimulate the immune system
• Ipilimumab—A monoclonal antibody that uses a checkpoint blockade strategy to maintain activated tumor-specific T-cells by neutralizing CTLA4, a coinhibitory receptor
• ¹⁷⁷Lu-J591 —A radiolabeled monoclonal antibody that binds to prostate-specific membrane antigens, which are expressed on virtually all prostate cancer cells, and triggers antibody-dependent cell-mediated cytotoxicity

With such a bounty of new technologies, Gomella said a prime consideration will be how to integrate immunotherapies into treatment timelines.

“That’s the hot button right now—combining these agents together,” he said. ‘Is there a rationale to combining sipuleucel-T with radiation, for example? Is there a rationale to combine it with chemotherapy? Should it be done before chemotherapy or after chemotherapy?

“All of these things are very exciting,” said Gomella. He said a prime focus in the next five years would involve sequencing—”where these immunotherapies fit in with our standard hormonal treatments and our cytotoxic chemotherapy treatments, and determining the best way to fit in an immunotherapy regimen.”

“That really remains to be seen,” he said.

As far as cost factors are concerned, Gomella put the expense of using sipuleucel-T to treat patients into a broader perspective of developing and administering cancer therapies. He noted that although the initial cost of sipuleucel-T treatment is high, overall costs with other modalities that may stretch on for months or years may be higher.

“I think what people have to step back and realize is that sipuleucel-T just did not arrive on the doorstep two or three years ago. The whole sipuleucel-T story goes back to the mid-1990s, so there’s been 10 to 15 years’ work of not only basic science research, but clinical trials to back its approval by the FDA,” said Gomella.

“These are very expensive therapies that we’re getting involved with. And, unfortunately, the cost of doing business to develop these products and bring them into the marketplace is also very costly,” he said. “A lot of drugs go into development that never go anywhere, but when you get one that works, you need to really put your support behind it.”

Robert L. Kirkman, MD

President Chief Executive Officer Oncothyreon Seattle, WA

Robert L. Kirkman, MD, formerly chief of the Division of Transplantation at Brigham and Women’s Hospital in Boston, Massachusetts, has been a biopharmaceutical executive since the late 1990s. In 2006, he took the helm of Oncothyreon in Seattle, Washington.

The company’s experience provides a glimpse at the manner in which one promising vaccine candidate is winding its way toward patients.

Oncothyreon has in its portfolio Stimuvax (BLP25), a vaccine for non-small cell lung cancer (NSCLC), a difficult disease state for immune-based therapies. An intravenously administered agent that uses a liposomal formulation, Stimuvax is aimed at inducing an immune response in cancerous cells that express the protein antigen MUC1.

Stimuvax has been in various stages of development for more than a decade, and now is entering the later stages of a phase III trial that has been under way for five years.

Oncothyreon recently raised approximately $50.3 million through a stock offering, yet it is a small company that had 32 employees and nearly $24.7 million in losses last year.⁶ The company has partnered with an international giant, Merck KGaA in Darmstadt, Germany, which is conducting the pivotal phase III START trial in more than 30 countries.

“It has completed enrollment of just over 1500 patients, and it has had two interim looks so far, both of which had efficacy and futility analyses performed. At both occasions, the Data Monitoring Board recommended that the trial continue. So we are in the final phases of this trial now,” said Kirkman. “The guidance that Merck has given is that the top-line data from this trial should be available in the first part of next year.”

The START trial is evaluating the vaccine in patients with unresectable stage IIIA/B NSCLC who have had a response or stable disease after at least two cycles of platinum-based chemoradiation. In addition, Stimuvax is being tested in approximately 420 patients in Asian countries with a similar histology through the phase III INSPIRE trial.

Key results came from a phase IIB study involving 171 patients. Stimuvax demonstrated a 17.3-month median survival advantage for patients treated with the vaccine plus best standard of care versus those who received best standard of care alone (30.6 months vs 13.3 months, respectively), according to Oncothyreon.

“Importantly, both of these trials have a number of very long-term survivors,” said Kirkman. “There are eight or nine patients from the original phase II, a trial which was finished back in 2003, who are still alive today. And in our comparability trial, about half of those patients were still alive at five years.

“Both of those numbers are way in excess of what you would normally expect in that disease setting,” he said. “That’s why we’re all excited to get the results of the START trial and hoping that they’re confirmatory. We’ll know in about eight months.”

When it comes to the immunotherapy field as a whole, Kirkman believes researchers remain excited about its possibilities, but that enthusiasm does not necessarily translate to raising capital.

“The investor world is a little fickle and waxes and wanes on the subject,” said Kirkman. “It took a very long time for anything to actually get approved, and we now have two approved immunotherapy products, Provenge for prostate cancer and Yervoy for melanoma, and that certainly has helped the field immensely.

“Over the next 12 months, we’re going to get a number of additional phase III immunotherapy trials coming to a conclusion,” noted Kirkman. “If one or more of those is successful, then it will pretty much answer the question that immunotherapy works. And I’m hoping that Stimuvax is one of those compounds.”

References

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2. Fox BA, Schendel DJ, Butterfield LH, et al. Defining the critical hurdles in cancer immunotherapy [commentary]. J Transl Med. 2011;9:214-228.
3. Galon J, Pagès F, Marincola FM, et al. The immune score as a new possible approach for the classification of cancer [editorial]. J Transl Med. 2012;10:1-4.
4. Dendreon Corp Form 10-K (Annual Report). Dendreon website. http://investor.dendreon.com/sec.cfm. Published February 29, 2012. Accessed June 10, 2012.
5. Nabhan C, Gomella LG, DeVries T, et al. An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study. J Clin Oncol. 2012;30(suppl 5;abstr 144).
6. Oncothyreon 2011 Annual Report. Oncothyreon website. http://ir.oncothyreon.com/annuals.cfm. Published March 9, 2012. Accessed June 11, 2012.