Immunotherapy Hits New Peak: ASCO Data Stir Excitement, Investment

OncologyLive, July 2013, Volume 14, Issue 7

In Partnership With:

Partner | Cancer Centers | <b>Rush University Cancer Center</b>

Any lingering skepticism about immunotherapy as an anticancer strategy appears to have been banished by research presented at the 2013 ASCO Annual Meeting.

Any lingering skepticism about immunotherapy as an anticancer strategy appears to have been banished by research presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting, with fresh data from several key trials translating into excitement in clinical circles and in the investment arena.

The most promising results came from an emerging class of antibodies that target the programmed death-1 (PD-1) pathway to take the brakes off the patient’s immune system, employing the same type of “checkpoint blockade” approach that ipilimumab (Yervoy) pioneered in metastatic melanoma.

With the monoclonal antibody nivolumab leading the field, the PD-1 pathway agents have been most effective in melanoma, but also are making an impact in non-small cell lung cancer and renal cell carcinoma. Some researchers are calling it a “breakthrough strategy.”

Yet researchers and pharmaceutical industry analysts say the excitement over immunotherapy extends to other strategies under investigation, which include vaccines and gene therapies, although perhaps with not as much enthusiasm as the checkpoint blockers have generated.

For longtime believers in the potential for immunotherapy, it is a time for celebration.

James P. Allison, PhD

“There is a great sense of gratification because for many, many years I’ve had the conviction that despite what seemed to be frustrations, there was a way of getting it to work if we just studied mechanisms enough,” said James P. Allison, PhD, whose research led to the FDA’s approval of ipilimumab in 2011, in an interview. “I think that these advances show that it really can work, and I think offer a great opportunity for saving a lot of lives.”

Allison, who is professor and chair of The University of Texas MD Anderson Cancer Center Department of Immunology, is particularly enthusiastic about the prospect of combining checkpoint blockers with each other and using these agents sequentially or in combination with targeted therapies.

He noted the results of phase I research presented at ASCO in which nivolumab was combined with ipilimumab, which blocks CTLA-4, leading to deep tumor regression in approximately one-third of patients with nonresectable stage III or IV melanoma.1

Allison said the field of immunotherapy needs to move forward, not only in the area of combination checkpoint blockers but also in the discovery of reagents that target other regulatory molecules on T-cells. When such inquiries are joined with the fields of genomics and targeted therapies, “then I think that we are going to see some real, real progress and very rapidly,” he said.

Jedd D. Wolchok, MD, PhD

Jedd D. Wolchok, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City who presented the nivolumab/ipilimumab combination research, is similarly optimistic.

Many Therapies Under Study

“For those of us who have been investigating means to use the immune system to treat cancer for decades, this is a glorious time,” said Wolchok. “We now have multiple medicines which are very precisely designed to interact with different on and off systems that the immune system uses to control T cells and antibodies. We’re now seeing the benefits with significant numbers of patients having very durable regressions.”More than 30 clinical trials involving nearly as many immunotherapy agents have reached the phase III stage, according to the Cancer Research Institute, a New York City nonprofit that provides funding to scientists in the field.

Many of these trials are evaluating ipilimumab in various settings. In melanoma, these include separate studies that compare treatment with and without ipilimumab in combinations with interferon alfa-2b, dacarbazine, or nivolumab. Other studies are looking at ipilimumab in combination with etoposide and platinum therapy versus those two drugs alone in small cell lung cancer, and at adding ipilimumab to paclitaxel and carboplatin versus that standard in squamous, non-small cell lung cancer. Ipilimumab also is under investigation versus placebo in separate clinical trials for patients with castration-resistant prostate cancer.

The new PD-1 antibodies also are moving quickly into clinical development. There are six phase III studies involving nivolumab. And, in a study that was just registered on in May, lambrolizumab (MK-3475) will be compared with ipilimumab in a three-arm advanced melanoma trial.

Howard L. Kaufman, MD

Although the checkpoint blockers have attracted much interest, there are many other approaches under investigation. “Immunotherapy in general does come in flavors,” said Howard L. Kaufman, MD, professor at Rush University Medical Center in Chicago, Illinois, and vice president of the Society for Immunotherapy of Cancer, in an interview.

FDA investigators broadly classify anticancer immunotherapies into three categories: (1) active immunotherapies, such as therapeutic vaccines; (2) adoptive cellular immunotherapy such as T- and B-cell transfer therapies, stem cell therapies, or gene-modified cells; and (3) passive immunotherapies, such as the administration of antibody or receptor ligands.2

Notably, Allison does not consider the checkpoint blockers, which are antibodies, to be passive immunotherapies; he said that description more accurately applies to such anticancer antibodies as rituximab.

Kaufmann said oncolytic viruses are “a brand new area,” with talimogene laherparepvec (T-VEC) as the most advanced in development (Read more >>>). He is the principal investigator on the OPTiM trial, which compares T-VEC that is injected directly into the lesions with granulocyte-macrophage colony-stimulating factor in advanced, unresectable melanoma.

“These viruses directly kill the tumor cells, which leads to one mode of action, and then we believe that an immune response can be generated with these as well, and that could lead to regression of distant disease.” Kaufman said. “This year for the first time we have a randomized, prospective phase III trial that has actually shown a benefit in terms of improving durable response rates in patients with melanoma.”

Financial Predictions Rosy

Although the virus approach has been studied mainly in melanoma thus far, Kaufman believes it could be effective in other tumor types as well.As with other medicines, many immunotherapies have faltered in later stages of clinical trials and investors often have been wary to fund such research. Now, however, momentum for expanded investment appears to be building.

In May, analysts at Citigroup Global Markets forecast that immunotherapy would become the “backbone” of treatment for up to 60% of tumor types over the next 10 years, making the field a $35 billion-a-year industry by 2013.

The prediction, included in a report titled ”Immunotherapy— The Beginning of the End for Cancer,” helped fuel enthusiasm in financial circles heading into the 2013 ASCO Annual Meeting, which was held May 31-June 4 in Chicago.

Michael G. King, Jr

Anticipation over the research into PD-1 pathway agents had been building in advance of the ASCO conference and “expectations clearly were satisfied,” Michael G. King, Jr, managing director and senior biotechnology analyst at JMP Securities in New York City, said in an interview.

He said nivolumab has attracted the most interest, followed by lambrolizumab and MPDL3280A. Although ipilimumab has made the checkpoint blockade strategy familiar, the anti-PD-1/ PDL1 agents have demonstrated high response rates and durability of responses, with more attractive safety profiles than ipilimumab.

“That all adds up to a very attractive economic framework,” King said. “It’s sort of a race to the top among the analysts as to just how big the category could be. You can come up numbers that seem crazy but when you think about it they’re not so crazy.”

Michael D. Becker

Thus far, Bristol-Myers Squibb, which developed ipilimumab and now nivolumab, has been the major beneficiary. The company’s shares increased about 20% from the time the ASCO abstracts were made public on May 15 through June 3, noted Michael D. Becker, president of MDB Communications LLC, in Newtown, Pennsylvania, who analyzed the cancer immunotherapy field in his Life Science Digest newsletter in July.3

Becker observed that smaller biotechnology companies, often with market capitalization values below $300 million, historically have been tackling cancer vaccine development. Now, however, pharmaceutical giants are engaging in research, Becker said. In addition, he said, many of the therapies take into account limits of prior agents.

“The era of skepticism over use of the body’s immune system to effectively treat cancer has officially come to an end,” Becker wrote. “We are now firmly in the early stages of the cancer immunotherapy revolution.”

Realizing Results

If a revolution is under way, then Charles J. Link Jr, MD, can be counted among those battling in the trenches.

Link is the founder and chief executive officer of NewLink Genetics, a biopharmaceutical company based in Ames, Iowa. A former medical oncology clinical fellow at the National Cancer Institute, Link served as the director of the John Stoddard Cancer Research Institute in Des Moines from 1995 to 2003.

Charles J. Link Jr, MD

He has been working on the cancer vaccine whose phase II results were presented at ASCO for nearly 17 years, he said in an interview.

NewLink has developed its own core technology, called HyperAcute, which can be used with different human cancer cell lines for tumor-specific vaccines. At ASCO, researchers presented the results of a clinical trial involving its lead agent, algenpantucel-L, in patients with resected pancreatic cancer.4

“It is a whole-cell, allogeneic vaccine, which means it’s a cell that does not come from the patient but is an off-the-shelf cell line that we engineer and grow,” said Link.

“The technology is based on a carbohydrate difference between humans and other animals,” he said, referring to alpha-gal. “There is a carbohydrate that the human immune system recognizes as a danger signal and attacks it with pre-existing antibodies. So all of us already have high levels of pre-existing antibodies against this carbohydrate. The technology genetically engineers that carbohydrate into human cancer cells to trigger these pre-existing immune responses that exist in humans already to educate the body against pancreatic cancer.”

In the study, 69 patients received the vaccine along with the standard of care, which consisted of gemcitabine with 5-FU modulated radiation therapy. After three years’ follow-up, the long-term disease-free survival and overall survival (OS) rates are 26% and 39%, respectively. Moreover, evaluable patients with elevated levels of anti-mesothelin antibodies achieved a median OS of 42 months versus 20 months in patients without the elevated levels, pointing the way toward a useful biomarker.

Now, a phase III trial involving more than 700 patients at 75 sites is expected to finish accrual this year, said Link.

In addition, the company has an earlier-stage development program focused on IDO pathway inhibitors, which also are checkpoint blockers similar to ipilimumab and the emerging PD-1 agents.

As one measure of the new landscape for cancer immunotherapy, NewLink was able to raise $49 million from a stock offering in February, according to the company’s website.

It was not so easy to raise money four or five years ago, Link noted.

“We think in companies that are showing clinical data in the immunotherapy space it’s beginning to get the same respect as the chemotherapy agents or new kinase inhibitors,” said Link. Immunotherapies, he added, are “going to be important for patients, and if they’re going to be important for patients they’re going to be important for investors.”

Table. Ongoing Phase III Immunotherapy Clinical Trials



Tumor Type



Autologous dendritic cell


Argos Therapeutics

BioVaxID (BV301)

Autologous immunoglobulin idiotype

Follicular lymphoma

Biovest International


Epithelial growth factor antigen


Bioven Europe


Autologous dendritic cells

Glioblastoma multiforme

Northwest Biotherapeutics


Telomerase peptide


Kael-GemVax Co, Ltd

HyperAcute-Pancreas (algenpantucel-L)

Alpha-gal-modified cancer cells


NewLink Genetics Corporation




immatics Biotechnologies GmbH

Imprime PGG

β-glucan bound to neutrophils



Lambrolizumab (MK-3475)

Anti-PD-1 monoclonal antibody



L-BLP25 (formerly Stimuvax)

MUC-1 peptide liposomal


Oncothyreon/Merck KgaA

Lucanix (belagenpumatucel-L)

Gene-modified TGF-β blocker


NovaRx Corporation

MAGE-A3 (astuprotimut)


Melanoma; NSCLC


Multikine (leukocyte interleukin)

Cytokine mixture

Oral cavity/soft palate

CEL-SCI Corporation


Autologous, hapten-modified


Avax Technologies

NeuVax (nelipepimut)

E75 peptide plus GM-CSF

Breast cancer

Galena Biopharma, Inc

Nivolumab (BMS-936558)

Anti-PD-1 monoclonal antibody

Melanoma; NSCLC; RCC

Bristol-Myers Squibb


Melanoma cell line antigens


Polynoma LLC




Advantagene, Inc


Poxviruses plus costimulatory molecules


Bavarian Nordic

Rindopepimut (CDX-110)

EGFRv3-specific peptide conjugated to KLH


Celldex Therapeutics

Talimogene laherparepvec (T-VEC)

Genetically modified herpes oncolytic virus



Vaxira (racotumomab)

Anti-idotypic monoclonal antibody


Recombio SL

Yervoya (ipilimumab)

Anti-CTLA-4 monoclonal antibody

Melanoma; NSCLC; prostate

Bristol-Myers Squibb


Cancer Research Institute,, company websites

aFDA-approved agent

GM-CSF indicates granulocyte macrophage colony stimulating factor; KLH, keyhole limpet hemocyanin; MHC, major histocompatibility complex; MUC, mucin; TGF, transforming growth factor; RCC, renal cell carcinoma; NSCLC, non-small cell lung cancer.


  1. Wolchok JD, Kluger HM, Callahan MK, et al. Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). J Clin Oncol. 2013;31(suppl; abstr 9012).
  2. Vatsan RS, Bross PF, Liu K, et al. Regulation of immunotherapeutic products for cancer and FDA’s role in product development and clinical evaluation. J Immunother Cancer. 2013;1:5. Accessed July 18, 2013.
  3. Becker, MD. Recognizing the disruptive potential of cancer immunotherapy. Life Science Digest. Published July 7, 2013. Accessed July 18, 2013.
  4. Rossi GR, Hardacre JM, Mulcahy MF, et al. Effect of algenpantucel-L immunotherapy for pancreatic cancer on anti-mesothelin antibody (Ab) titers and correlation with improved overall survival. J Clin Oncol. 2013;31 (suppl; abstr 3007).