CTLs attacking cancer cells.


On September 15, 2017, Bavarian Nordic’s Phase 3 trial of its cancer vaccine Prostvac ended in failure. Prostvac failed to improve overall survival in patients with metastatic castration-resistant prostate cancer, as determined by the clinical trial.

We had listed Prostvac in Chapter 5 and in Table 5-2 of our 2017 report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, as a cancer vaccine that was in Phase 3 clinical trials. However, as we stated in that chapter, “It is possible that one or more of the experimental agents listed in Table 5-2 may [also] experience late-stage failure.” That is because the cancer vaccine field has been subject to a high rate of clinical failure, including several late-stage failures in 2016.

Despite the high rate of failure in the cancer vaccine field, there are now two FDA approved cancer vaccines— sipuleucel-T (Dendreon/Valeant’s Provenge) and talimogene laherparepvec (Amgen’s Imlygic/T-Vec), the latter of which is an oncolytic virus, rather than a true cancer vaccine. However, both of these agents are rather marginal therapies. Sipuleucel-T has an apparently minimal effect and is very expensive and difficult to manufacture. T-Vec must be injected directly into a tumor, and as a monotherapy, there is no evidence for improvement of overall survival or effects on distant metastases. However, researchers have hypothesized that as a directly-injected agent, T-Vec might produce an inflammatory tumor microenvironment that will provide an ideal target for checkpoint inhibitors. Thus, researchers have had expectations that combination therapies of T-Vec with checkpoint inhibitors which are now in progress may yield much better results.

Indeed, on October 6, 2017, a peer-reviewed Phase 2 published study indicates that a combination of Imlygic and Bristol-Myers Squibb’s (BMS’) CTLA4 checkpoint inhibitor Ipilimumab (Yervoy) doubles response rates in advanced melanoma as compared to Yervoy alone. The published trial results show that the objective response rate for the combination was 39%, compared to 18% for Yervoy alone. With respect to complete responses, the combination gave13% as compared to 7% for Yervoy alone. Responses occurred in patients with and without visceral disease and in uninjected lesions after combination treatment, according to the study.

Amgen’s head of R&D, Sean E. Harper MD says that the trial provides an important proof-of-concept for combining the complementary mechanisms of an oncolytic viral immunotherapy and a checkpoint inhibitor to enhance antitumor effects, adding that the company intends to test Imlygic in combination other checkpoint inhibitors in “a variety of tumor types”.

Imlygic—in combination with another checkpoint inhibitor, pembrolizumab (Merck’s PD-1 inhibitor Keytruda)—is in a Phase 3 trial (KEYNOTE-034, clinical trial number NCT02263508) in advanced melanoma. This trial is expected to yield preliminary results in 2018. In 2014, the Phase 1b/2 MASTERKEY-256 trial of the Imlygic/Keytruda combination in advanced melanoma showed an overall response rate (ORR) of around 56%.

These data indicate that the immunotherapy 2.0 strategy of using Imlygic to generate an inflammatory tumor microenvironment may produce a synergistic clinical effect and enhanced anti-tumor immune response in patients with metastatic melanoma who are also treated with a checkpoint inhibitor.

As we discuss in Chapter 5 of our 2017 Cancer Immunotherapy report, several cancer vaccine developers are pursuing a similar strategy—use cancer vaccines to render tumors inflamed [i.e. especially with cytotoxic tumor-infiltrating lymphocytes (TILs)], and use checkpoint inhibitors to induce regression of the inflamed tumors. In some cases, cancer vaccines are being tested in combination with checkpoint inhibitors in Phase 1 or Phase 2 clinical trials, rather than the “traditional” approach of first getting a vaccine approved and then conducting trials of the vaccine in combination with other agents. The hope is that testing a vaccine in combination with a checkpoint inhibitor in early stage clinical trials might prevent clinical failure of a potentially useful cancer vaccine. However, whether this strategy will work for any particular vaccine remains to be seen.

Neoantigen cancer vaccines

Another novel immunotherapy 2.0 strategy for cancer vaccine discovery and development discussed in our report involves neoantigen science. Recent studies exploring mechanisms by which TILs and other components of the immune system recognize tumor cells and differentiate them from noncancer cells have focused on “neoantigens”—i.e. antigens that are specific for cancer cells as opposed to normal, noncancer cells. These neoantigens are associated with somatic mutations that arise in the evolution of tumor cells. Neoantigen-specific TILs appear to mediate tumor regression, and this antitumor activity may be enhanced by checkpoint inhibitor therapy. Such studies have led researchers to hypothesize that personalized neoantigen-based vaccines may be more effective than earlier types of cancer vaccines. Some researchers have therefore been attempting to develop technology platforms for vaccine design based on determination of neoantigens in tumors.

In particular, neoantigen researchers at the Dana-Farber Cancer Institute, the Broad Institute, Massachusetts General Hospital, and Brigham and Women’s Hospital recently founded a company, Neon Therapeutics (Cambridge, MA). Neon focuses on neoantigen science and technology for the development of neoantigen-based therapeutic vaccines and T-cell therapies to treat cancer.

These researchers published a report in the 13 July issue of Nature describing their Phase 1 study in patients with previously untreated high-risk melanoma of a personalized neoantigen vaccine designated NEO-PV-01 by Neon Therapeutics and in Chapter 5 of our report.

As discussed in our report, Neon’s lead clinical program, NEO-PV-01, builds upon initial clinical trials developed collaboratively by the Broad Institute and the Dana-Farber. NEO-PV-01 is a personalized vaccine that is custom-designed and manufactured to include targets for the immune system [i.e. naturally-processed, major histocompatibility complex (MHC)-binding, neoantigen peptide epitopes] that are unique to an individual’s cancer. The 13 July Nature report focuses on results of the ongoing Phase 1 clinical trial designated NCT01970358 of the combination of poly-ICLC [poly-inosinic acid/poly-cytidylic acid/poly-lysine, an adjuvant] and multiple neoantigen peptide epitopes in melanoma.

As discussed in that Nature paper, neoantigens were long envisioned as optimal targets for anti-tumor immune responses. However, the systematic identification of neoantigens in a particular patient’s tumors only became feasible with the availability of massively parallel sequencing for detection of coding mutations, and of machine learning technology to reliably predict those naturally-processed mutated peptides that bind with high affinity to autologous major histocompatibility (MHC) molecules. (The term “naturally-processed” refers to antigenic peptide epitopes that are processed intracellularly and which bind with high affinity to autologous class I or class II MHC molecules. The MHC/peptide complexes are then recognized by T cells.)

In the study described in the 13 July Nature paper, the researchers demonstrated the feasibility, safety, and immunogenicity of a vaccine (designated NEO-PV-01 as discussed earlier), which targets up to 20 predicted personal tumor neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of 97 unique neoantigens across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumor. Of six vaccinated patients, four had no recurrence as of 25 months post-vaccination. Two other patients who had recurrent disease were subsequently treated with the anti-PD-1 antibody pembrolizumab (Merck’s Keytruda). These two patients experienced complete tumor regression, with expansion of the repertoire of neoantigen-specific T cells.

These results strongly support further development of the researchers’ neoantigen vaccine approach, both alone and in combination with checkpoint inhibitors or other immunotherapies. Neon Therapeutics is currently sponsoring an open-label Phase 1b clinical study of NEO-PV-01 plus adjuvant in combination with nivolumab (BMS’ Opdivo) in patients with melanoma, smoking-associated non-small cell lung carcinoma (NSCLC) or transitional cell bladder carcinoma (clinical trial number NCT02897765). Neon entered into a collaboration with BMS to perform this clinical trial in late 2015.

Neon is also developing NEO-PTC-01, a personal neoantigen autologous T cell therapy, which is now in the research and process development stage. As discussed in Chapter 6 of our 2017 cancer immunotherapy report, neoantigen science is also a factor in adoptive cellular immunotherapy for cancer, especially in Steven A. Rosenberg MD, PhD’s recent studies of TIL therapy.

Other neoantigen cancer vaccine companies

In addition to Neon, other young companies that specialize in development of neoantigen-based cancer vaccines include BioNTech AG (Mainz, Germany), Gritstone Oncology (Emeryville, CA and Cambridge, MA), ISA Pharmaceuticals (Leiden, The Netherlands), Agenus (Lexington, MA), and Caperna (Cambridge, MA). Of these companies, BioNTech and Caperna [which is a Moderna (Cambridge, MA) venture company] are developing RNA-based personalized neoantigen vaccines. The other companies are developing peptide neoantigen vaccines based on their proprietary technologies.


As discussed in this article, and in our 2017 report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, researchers and developers are applying several immunotherapy 2.0 approaches to attempt to reverse the high rate of failure in the cancer vaccine field.

Moreover, neoantigen science has a potentially wide field of application, ranging from improving clinical outcomes of treatments with checkpoint inhibitors to development of more effective cancer vaccines and of novel cellular immunotherapies.

Our report contains materials designed to enable readers to understand complex issues in neoantigen science, and especially to understand applications of neoantigen science in research reports, clinical trials, corporate news, and product development.

For more information on our report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, or to order it, see the CHI Insight Pharma Reports website.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

PD-1 extracellular domain


As noted in our 2017 Insight Pharma Report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes” the most successful class of immunotherapeutics continues to be that of the checkpoint inhibitors (discussed in Chapter 2 of our report).

Immune checkpoints refer to a large number of inhibitory pathways in the immune system, especially those that block the response of T cells to antigens. Marketed checkpoint inhibitors are all monoclonal antibodies (mAbs). The two leading checkpoint inhibitors, both of which target PD-1, are pembrolizumab (Merck’s Keytruda), and nivolumab, (Bristol-Myers Squibb’s Opdivo), both approved by the FDA in 2014. Of these two, Keytruda has become the market leader during 2016/2017, after a long process of competition with BMS’ Opdivo..

On July 26, 2017, Forbes published a long article by David Shaywitz MD, PhD, entitled “The Startling History Behind Merck’s New Cancer Blockbuster”. This article is a complete history of Keytruda, from discovery through commercialization. As discussed in this article, Roger Perlmutter MD PhD (who became head of Merck Research Labs during the process of development of Keytruda) redirected virtually all work at Merck towards the Keytruda program. He determined that Keytruda was more valuable than the entire rest of Merck’s portfolio put together. Dr. Perlmutter essentially bet both his own career and Merck’s enterprise on the Keytruda program.

Merck has been engaging in an aggressive R&D and commercialization program for Keytruda. In the second quarter of 2017, Keytruda achieved three accelerated approvals and one full approval in the U.S., a recommendation in the EU, and a 180% increase in sales. As of September 2017, Merck has over 550 clinical trials evaluating Keytruda in more than 30 tumor types.

As expected for such an aggressive program, not all of Merck’s efforts have been successful. Three of the company’s combination trials of Keytruda, with Celgene’s Revlimid (lenalidomide) or Pomalyst (pomalidomide) plus dexamethasone in multiple myeloma, have been on hold because of an excess number of deaths in the treatment arm. Merck also had a missed endpoint in recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-040 trial. Despite this, Keytruda has held onto its accelerated approval for this indication, and other HNSCC trials are ongoing.

Merck’s acquisition of Rigontec

Keytuda has become as much a platform as a product for Merck. This is illustrated by the recent acquisition by Merck of the German company Rigontec for $150 million in cash and another $453 million in milestones payments. According to John Carroll’s Endpoints News, this is an example of how Merck’s Perlmutter likes to augment the work being done around Keytruda with the occasional add-on.

Mr. Carroll refers to the Rigontec deal as a “bolt-on” acquisition. In a “bolt-on” acquisition, a platform company (such as Merck) with the management capabilities, infrastructure and systems that allows for organic or acquisition growth will look for acquisition of smaller companies “that provide complementary services, technology or geographic footprint diversification and can be quickly integrated into the existing management infrastructure.”

Rigontec’s technology platform is based on developing agents that mimic viral infections. Specifically, double-stranded viral RNA is recognized by pattern recognition receptors called RIG-I-like helicases (RLH) that are present in the cytoplasm. Synthetic RLH ligands (such as those being developed by Rigontec) working via RLH initiate a signaling cascade that leads to an antiviral response program, characterized by the production of type I interferon (IFN) and other innate immune response genes. RLH signaling also induces apoptosis in tumor cells. Finally, exposure of CD8alpha+ dendritic cells (DCs) to RLH-activated apoptotic tumor cells induces DC maturation, efficient antigen uptake and cross-presentation of tumor-associated antigens to naive CD8+ T cells.

The exploitation of the RLH system thus constitutes a potential means to activate tumor-specific CD8+ T cells. As discussed in our 2017 Insight Pharma report, checkpoint inhibitors work by reactivating intratumoral T-cells, especially CD8+ cytotoxic T cells. Rigontec’s agents may work to render “cold” tumors inflamed (specifically, with DCs and CD8+ T cells), thus making them more susceptible to the antitumor action of checkpoint inhibitors such as Keytruda. This type of strategy, as discussed in our report, is a major theme of “second wave” immuno-oncology, or “immuno-oncology 2.0.”

However, so far the potential use of Rigontec’s RLH ligands in cancer therapy is based on studies in preclinical tumor models for melanoma, ovarian cancer and pancreatic cancer. Currently, Rigontec has been sponsoring a first-in-humans Phase 1/2 trial of its lead RIG-1 agonist, RGT100, in solid tumors and lymphoma (clinical trial number NCT03065023). This study is designed to assess “safety, tolerability and pharmacokinetics of RGT100 in patients with injectable solid tumor lesions”. In the absence of evidence for clinical efficacy in human cancer patients, the Merck acquisition of Rigontec is a speculative deal. However, upfront Merck’s investment in Rigontec is small, and it gives Merck access to a new mechanism of action, which is complementary to the larger company’s strategy and current pipeline.

Other immunotherapy 2.0 approaches designed to enhance the effectiveness of checkpoint inhibitors

As noted in our 2017 Insight Pharma Report, although checkpoint inhibitors such as Keytruda have achieved spectacular success in treating some patients, they do not work for the majority of patients. Even in the case of melanoma, where checkpoint inhibitors have shown the greatest degree of efficacy, these agents only cure 20% of patients. Therefore, numerous researchers and companies are working to discover and develop complementary “immunotherapy 2.0” treatments to enhance the efficacy of checkpoint inhibitors in various classes of cancer patients. Rigontec’s technology represents only one such approach.

In a recent article published (Sep 7, 2017) in FierceBiotech, writer Arlene Weintraub discussed two companion treatments that might potentially enhance the effectiveness of checkpoint inhibitors. One of these treatments, discovered by scientists at Columbia University Medical Center, is a drug that’s already on the market: pentoxifylline, which is used to increase blood flow in patients with poor circulation. Pentoxifylline’s activity in cancer immunology is based on its inhibition of NF-kB c-Rel.  This results in the inhibition of regulatory T cells (Tregs) in the tumor mcroenvironment. In mouse models, inhibition of c-Rel function by pentoxifylline delayed melanoma growth by impairing Treg-mediated immunosuppression, and thus and potentiated the effects of anti-PD-1 immunotherapy. Adverse effects, such as the induction of autoimmunity that would be expected if the treatment caused global inhibition of Tregs, were not seen. Once again, these studies in mice await confirmation via human clinical trials; such human trials are currently planned.

The other experimental immunotherapy 2.0 approach discussed in Ms. Weintraub’s article involves combining an oncoloytic virus [the modified vaccinia virus Ankara (MVA)] with a checkpoint inhibitor. Once again, the example discussed in this article was in mouse models. As in other immunotherapy 2.0 approaches, the goal is to enable the immune system to recognize the tumor as foreign by injecting the oncolytic virus into it, thus prompting a CD8+ T-cell response. Checkpoint inhibitors might then reactivate the intratumoral T cells, inducing an antitumor response. These studies were also carried out in mouse models, and human trials are planned.

Our report, “Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes”, also includes discussions of the use of oncolytic viruses to boost the anticancer efficacy of checkpoint inhibitors. Some of these approaches (such as studies of combinations of Amgen’s Imlygic (talimogene laherparepvec), an FDA-approved modified oncolytic virus therapy, with checkpoint inhibitors), are already in human studies.

Also in our report is a discussion of treatments being developed by NewLink Genetics designed to modulate the IDO (indoleamine-pyrrole 2,3-dioxygenase) pathway. Such compounds are designed to reverse IDO-mediated immune suppression. IDO pathway inhibitors may complement the use of anti- PD-1and/or anti-PD-L1 checkpoint inhibitors. The same Endpoints News article that discusses the Merck/Rigontec acquisition  also mentions an earlier Merck bolt-on deal—the 2016 acquisition of IOmet. IOmet also works on IDO pathway inhibitors.

More generally, our 2017 Insight Pharma Report contains a wealth of potential immunotherapy 2.0 approaches. Importantly, this includes an “immunotherapy 2.0” approach to cancer vaccine development, which emphasizes combinations of cancer vaccines with checkpoint inhibitors. This may both enhance the efficacy of checkpoint inhibitors, and reverse the high rate of failure of cancer vaccines. Other immunotherapy 2.0 strategies discussed in our report may well make the news over the next several years, in terms of corporate deals and product approvals. Our report is thus well worth reading for those who are interested in the further devlelopment of immuno-oncology.

For more information on our report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, or to order it, see the CHI Insight Pharma Reports website.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Steven Rosenberg

Steven Rosenberg

On September 6, 2014, we published an article on this blog announcing the publication of our book-length report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, by Cambridge Healthtech Institute (CHI).

In that article, we cited the example of the case of a woman with metastatic cholangiocarcinoma (bile-duct cancer), which typically kills the patient in a matter of months. The patient, Melinda Bachini, was treated via adoptive immunotherapy with autologous tumor-infiltrating T cells (TILs) resulting in survival over a period of several years, with a good quality of life.

Our report includes a full discussion of that case, as of the date of the May 2014 publication of a report in Science by Steven A. Rosenberg, M.D., Ph.D. and his colleagues at the National Cancer Institute (NCI). Ms. Bachini’s story was also covered in a May 2014 New York Times article.

Now comes the publication, in Science on December 2015, of an update from the Rosenberg group on their clinical studies of TIL-based immunotherapy of metastatic gastrointestinal cancers. This article discusses the results of TIL treatment of ten patients with a variety of gastrointestinal cancers, including cancers of the bile duct, the colon or rectum, the esophagus, and the pancreas. The case of Ms. Bachini (“patient number 3737”) was included.

Ms. Bachini, a paramedic and a married mother of six children, and a volunteer with the Cholangiocarcinoma Foundation, was 41 years old when first diagnosed with cancer. She remains alive today—a five-year survivor—at age 46.

The Foundation produced a video, dated March 13, 2015, in which Ms. Bachini gives her “patient perspective”. This video includes her story “from the beginning”—from diagnosis through surgery and chemotherapy, and continuing with adoptive immunotherapy at the NCI under Dr. Rosenberg. Although her tumors continue to shrink and she remains alive, she still is considered to have “Stage 4” (metastatic) cancer. Ms. Bachini is a remarkable woman.

The Cholangiocarcinoma Foundation has also produced an on-demand webinar (dated October 21, 2014) on the adoptive cellular therapy trial in patients with various types of metastatic gastrointestinal cancers, led by Drs. Eric Tran and Steven Rosenberg. Ms. Bachini is also a presenter on that webinar. The December 2015 Science article is an updated version of the results of this trial.

The trial, a Phase 2 clinical study (NCT01174121) remains ongoing, and is recruiting new patients.

The particular focus of Dr. Tran’s and Dr. Rosenberg’s study in TIL treatment of gastrointestinal cancers is whether TILs derived from these tumors include T-cell subpopulations that target specific somatic mutations expressed by the cancers, and whether these subpopulations might be harnessed to successfully treat patients with these cancers. Of the ten patients who were the focus of the December 2015 publication, only Ms. Bachini had a successful treatment. In the case of Ms. Bachini, she received a second infusion of TILs that were enriched for CD4+ T cells that targeted a unique mutation in a protein known as ERBB2IP. It was this second treatment that resulted in the successful knockdown of her tumors, which continues to this day.

Despite the lack of similar successes in the treatment of the other nine patients, the researchers found that TILs from eight of these patients contained CD4+ and/or CD8+ T cells that recognized one to three somatic mutations in the patient’s own tumors. Notably, CD8+ TILs isolated from a colon cancer tumor of one patient (patient number 3995) recognized a mutation in KRAS known as KRAS G12D. This mutation results in an amino acid substitution at position 12 in KRAS, from glycine (G) to aspartic acid (D). KRAS G12D is a driver mutation that is involved in causation of many human cancers.

Although two other patients (numbers 4032 and 4069, with colon and pancreatic cancer, respectively) had tumors that expressed KRAS G12D, the researchers did not detect TILs that recognized the KRAS mutation in these patients. The researchers concluded that KRAS G12D was not immunogenic in these patients. The TILs from patient 3995 were CD8+ T cells that recognized KRAS G12D in the context of the human leukocyte antigen (HLA) allele HLA-C*08:02. [As with all T cells, TILs express T-cell receptors (TCRs) that recognize a specific antigenic peptide bound to a particular major histocompatibility complex (MHC) molecule—this is referred to as “MHC restriction”.] The two patients for whom KRAS G12D was not immunogenic did not express the HLA-C*08:02 allele.

The results seen with KRAS G12D-expressing tumor suggest the possibility of constructing genetically-engineered CD8+ T cells that express a TCR that is reactive with the KRAS mutation in the context of the HLA-C*08:02 allele. The KRAS G12D driver mutation is expressed in about 45% of pancreatic adenocarcinomas, 13% of colorectal cancers, and at lower frequencies in other cancers, and the HLA-C*08:02 allele is expressed by approximately 8% and 11% of white and black people, respectively, in the U.S. Thus, in the U.S. alone, thousands of patients per year with metastatic gastrointestinal cancers would potentially be eligible for immunotherapy with this KRASG12D-reactive T cell.

Although only Ms. Bachini (“patient number 3737”) was a long-term survivor, the researchers were able to treat three other patients with enriched populations of TILs targeting predominantly one mutated tumor antigen. Patient 4069 experienced a transient regression of multiple lung metastases of his pancreatic adenocarcinoma, but patients 4007 and 4032 had no objective response. Whereas 23% of circulating T cells at one month after treatment were adoptively transferred mutation-specific TILs in the case of Ms. Bachini, the other three patients treated with enriched populations of mutation-specific TILs showed no or minimal persistence. The researchers concluded that they will need to develop strategies designed to enhance the potency and persistence of adoptively transferred mutation-specific TILs. Nevertheless, the researchers concluded that nearly all patients with advanced gastrointestinal cancers harbor tumor mutation-specific TILs. This finding may serve as the basis for developing personalized adoptive cellular therapies and/or vaccines that can effectively target common epithelial cancers.


Dr. Rosenberg pioneered the study and development of adoptive cellular immunotherapy, beginning in the 1980s. Most studies with TIL-based adoptive immunotherapy have been in advanced melanoma. Adoptive cellular immunotherapy is the most effective approach to inducing complete durable regressions in patients with metastatic melanoma.

As we discussed in our cancer immunotherapy report, melanoma tumors have many more somatic mutations (about 200 nonsynonymous mutations per tumor) than most types of cancer. This appears to be due to the role of a potent immunogen—ultraviolet light—in the pathogenesis of melanoma. The large number of somatic mutations in melanomas results in the infiltration of these tumors by TILs that target the mutations. As discussed in our report, Dr. Rosenberg and his colleagues cultured TIL cell lines that addressed specific immunodominant mutations in patients’ melanomas. Treatment with these cell lines in several cases resulted in durable complete remissions of the patients’ cancers.

Dr. Rosenberg and his colleagues used the same strategy employed in identification of TIL cell lines that targeted specific mutations in melanomas to carry out the study in gastrointestinal cancers, as discussed in our report. However, the small number of somatic mutations and of endogenous TILs in gastrointestinal cancers and in most other epithelial cancers has made studies in these cancers more difficult than studies in melanoma.

in addition, the susceptibility of melanoma to treatment with checkpoint inhibitors such as the PD-1 blockers pembrolizumab (Merck’s Keytruda) and nivolumab (Bristol-Myers Squibb’s Opdivo) correlates with the large number of somatic mutations in this type of cancer. As we discussed in our December 15, 2014 article on this blog, immune checkpoint inhibitors work by reactivating endogenous tumor-infiltrating T cells (TILs). In the case of melanoma, these endogenous TILs target the numerous somatic mutations found in these cancers, and—as suggested by Dr. Rosenberg’s studies with cultured TIL cell lines—those endogenous TILs that target immunodominant mutations can induce durable compete remissions. As discussed in our December 15, 2014 blog article, the three major types of immuno-oncology treatments—immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies, work via related mechanisms.

In 2015, researchers showed that other types of cancers that have numerous somatic mutations are especially susceptible to checkpoint inhibitor treatment. These include, for example, non-small cell lung cancers (NSCLCs) that have mutational signatures that indicate that the cancers were caused by smoking, and cancers that have mutations in genes involved in DNA repair. (Mutations in genes involved in DNA repair pathways result in the generation of numerous additional mutations.)

Moreover, as discussed in our December 15, 2014 blog article, cancer immunotherapy researchers have been expanding the types of tumors that can be treated with checkpoint inhibitors. Genentech/Roche’s PD-L1 inhibitor that was discussed in that article, MPDL3280A, is now called atezolizumab. The clinical trials of atezolizumab discussed in that article and in our report have continued to progress. In a pivotal Phase 2 study in locally advanced or metastatic urothelial bladder cancer (UBC), atezolizumab shrank tumors in 27 percent of people whose disease had medium and high levels of PD-L1 expression and had worsened after initial treatment with platinum chemotherapy. These responses were found to be durable. According to Genentech, these results may represent the first major treatment advance in advanced UBC in nearly 30 years. Atezolizumab also gave positive results in Phase 2 clinical trials in patients with NSCLC that expresses medium to high levels of PD-L1.

Meanwhile, NewLink Genetics (Ames, IA) has entered Phase 3 clinical trials in pancreatic cancer with its HyperAcute cellular immunotherapy vaccine therapy. A Phase 2 trial of the company’s HyperAcute cellular immunotherapy algenpantucel-L in combination with chemotherapy and chemoradiotherapy in resected pancreatic cancer (clinical trial number NCT00569387) appears to be promising.

Dr. Rosenberg’s studies of TIL therapies of gastrointestinal cancers represent another approach to moving immuno-oncology treatments beyond melanoma, based on mutation-specific targeting. The types of cancers that form the focus of these studies—gastrointestinal epithelial cancers—have proven difficult to treat. Moreover, several of them are among the most common of cancers. The researchers and patients involved in these and other immuno-oncology studies are heroes, and oncologists appear to be making measured progress against cancers that have been until recently considered untreatable.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Pre-1917 Russian Happy Christmas and Happy New Year card

Pre-1917 Russian Happy Christmas and Happy New Year card

As is their customary practice, both Nature and Science ran end-of-year specials. The Nature special (in their 18 December issue) is entitled “365 days: Nature’s 10. Ten people who mattered this year.” The Science special (in their 19 December issue) is entitled, as usual “2014 Breakthrough of the Year.” As is also usual, there is a section for “Runners Up” to the year’s “Breakthrough”.

From the point of view of a consulting group—and a blog—that focuses on effective drug discovery and development strategies, we were disappointed with both end-of-year specials. Most of the material in these articles was irrelevant to our concerns.

Science chose the Rosetta/Philae comet-chasing mission as the “Breakthrough of the Year”, and its “runners up” included several robotics and space-technology items, as well as new “letters” to the DNA “alphabet” that don’t code for anything.

Nature also focused on comet chasers, robot makers, and space technologists, as well as cosmologist and mathematicians, and a fundraising gimmick—“the ice-bucket challenge”. Moreover, Nature was much too restrictive in titling its article “Ten people who mattered”. Every human being matters!

Nevertheless, these two special sections do contain a few gems that are both relevant to effective drug discovery and development, and are worthy of highlighting as “notable researchers of 2014” and “breakthrough research of 2014”. We discuss these in the remainder of this article.

Suzanne Topalian, M.D.

Suzanne Topalian is one of the researchers profiled in “Nature’s 10”. She is a long-time cancer immunotherapy clinical researcher who began her career in 1985 in the laboratory of cancer immunotherapy pioneer Steven Rosenberg at the National Cancer Institute (Bethesda MD). In the early days of the field, when cancer immunotherapy was scientifically premature, there was a great deal of skepticism that these types of treatments would even work. However, both Dr. Rosenberg and Dr. Topalian persevered in their research.

In 2006, Dr. Topalian moved to Johns Hopkins University (Baltimore, MD) to help launch clinical trials of Medarex/Bristol-Myers Squibb/Ono’s nivolumab, a PD-1 inhibitor. As noted in the Nature article, her work “led to a landmark publication in 2012 showing that nivolumab produced dramatic responses not only in some people with advanced melanoma but also in those with lung cancer [specifically, non–small-cell lung cancer, NSCLC].” We also discussed that publication on the Biopharmconsortium Blog, and in our recently published book-length Insight Pharma Report, Cancer Immunotherapy: immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies. Our report also includes discussions of Dr. Rosenberg’s more recent work in cellular immunotherapy.

As discussed in our report, nivolumab was approved in Japan as Ono’s Opdivo in July 2014 for treatment of unresectable melanoma, and a competitive PD-1 inhibitor, pembrolizumab (Merck’s Keytruda) was approved in the United States for advanced melanoma on September 5, 2014. More recently, on December 22, 2014, the FDA also approved nivolumab (BMS’ Opdivo) for advanced melanoma in the U.S. There are thus now two FDA-approved PD-1 inhibitors [in addition to the CTLA-4 inhibitor ipilimumab (BMS’ Yervoy)] available for treatment of advanced melanoma in the U.S.

Meanwhile, researchers continue to test both nivolumab and pembrolizumab for treatment of NSCLC and other cancers. And some analysts project that both of these agents are likely to be approved by the FDA for treatment of various populations of patients with NSCLC before the middle of 2015. Researchers are also testing combination therapies that include nivolumab or pembrolizumab in various cancers. And clinical trials of Genentech/Roche’s PD-L1 blocking agent MPDL3280A are also in progress.

Science’s 2013 Breakthrough of the Year was cancer immunotherapy, as we highlighted in our New Year’s 2014 blog article. Science could not make cancer immunotherapy the Breakthrough of the Year for 2014, too. Thus it chose to give physical scientists a turn in the limelight by highlighting the comet-chasing mission instead. Nevertheless, 2014 was the year in which cancer immunotherapy demonstrated its maturity by the regulatory approval of the two most advanced checkpoint inhibitor agents, pembrolizumab and nivolumab.

Implications for patients with terminal cancers

The clinically-promising results of cancer immunotherapy in a wide variety of cancers, coupled with the very large numbers of clinical trials in progress in this area, has also changed the situation for patients who have terminal cancers. Researchers who are conducting clinical trials of immunotherapies for these cancers are actively recruiting patients, of whom there are limited numbers at any one time. For example, there are now numerous clinical trials—mainly of immunotherapies—in pancreatic cancer, and most of these trials are recruiting patients. There are also active clinical trials of promising immunotherapies in the brain tumor glioblastoma. These are only two of many examples.

Recently, a 29-year-old woman with terminal glioblastoma ended her life using Oregon’s physician-assisted suicide law. Prior to her suicide, she became an advocate for “terminally ill patients who want to end their own lives”. We, however, are advocating that patients with glioblastoma and other types of terminal cancer for which there are promising immunotherapies seek out clinical trials that are actively recruiting patients. There is the possibility that some of these patients will receive treatments that will result in regression of their tumors or long-term remissions. (See, for example, the case highlighted in our September 16, 2014 blog article. There are many other such cases.) And it is highly likely that patients who participate in these trials will help researchers to learn how to better treat cancers that are now considered “incurable” or “terminal”, and thus help patients who contract these diseases in the future. From our point of view, that is a lot better than taking one’s own life via assisted suicide, and/or becoming an euthanasia advocate.

Masayo Takahashi, M.D., Ph.D.

Another researcher profiled in “Nature’s 10” is Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology (CDB) in Kobe, Japan who has been carrying out pioneering human stem cell clinical studies. We also discussed Dr. Takahashi’s research in our March 14, 2013 article on this blog.

At the time of our article, Dr. Takahashi and her colleagues planned to submit an application to the Japanese health ministry for a clinical study of induced pluripotent stem cell (iPS)-derived cells, which would constitute the first human study of such cells. They planned to treat approximately six people with severe age-related macular degeneration (AMD). The researchers planned to take an upper arm skin sample the size of a peppercorn, and transform the cells from this sample into iPS cells by using specific proteins. They were then to add other factors to induce differentiation of the iPS cells into retinal cells. Then a small sheet of these retinal cells were to be placed under the damaged area of the retina, where they were expected to grow and repair the damaged retinal pigment epithelium (RPE). Although the researchers would like to demonstrate efficacy of this treatment, the main focus of the initial studies was to be on safety.

According to the “Nature’s 10” article, such an autologous iPS-derived implant was transplanted into the back of a the damaged retina of one patient in September 2014. This patient, a woman in her 70s, had already lost most of her vision, and the treatment is unlikely to restore it. However, Dr. Takahashi and her colleagues are determining whether the transplant is safe and prevents further retinal deterioration. So far, everything has gone smoothly, and the transplant appears to have retained its integrity. However, the researchers will not reveal whether the study has been a success until a year after the transplantation.

The “Nature’s 10” article discusses how this technology might be moved forward into clinical use if the initial study is successful. It also discusses how Dr. Takahashi has been carrying her research forward in the face of a major setback that has plagued stem cell research at the CDB in 2014, as the result of the withdrawal of two once highly-regarded papers and the suicide of one of their authors.

Generation of insulin-producing human pancreatic β cells from embryonic stem (ES) cells or iPS

Another stem cell-related item, which was covered in Science’s end-of-2014 “Runners Up” article, concerned the in vitro generation of human pancreatic β cells from embryonic stem (ES) cells or iPS. For over a decade, researchers have been attempting to accomplish this feat, in order to have access to autologous β cells to treat type 1 diabetes, in which an autoimmune attack destroys a patient’s own β cells. In vitro generated β cells might also be used to screen for drugs that can improve β cell function, survival, and/or proliferation in patients with type 2 diabetes.

As reported in the Science article, two research groups—one led by Douglas A. Melton, Ph.D. (Harvard Stem Cell Institute, Cambridge, MA), and the other by Alireza Rezania, Ph.D. at BetaLogics Venture, a division of Janssen Research & Development, LLC.–developed protocols to produce unlimited quantities of β cells, in the first case from IPS cells, and in the other from ES cells.

However, in order to use the β cells to treat type 1 diabetes patients, researchers need to develop means (for example, some type of encapsulation) to protect the cells from the autoimmune reaction that killed patients’ own natural β cells in the first place. For example, Dr. Melton is collaborating with the laboratory of Daniel Anderson, Ph.D. (MIT Koch Institute for Integrative Cancer Research). Dr. Anderson and his colleagues have developed a chemically modified alginate that can be used to coat and protects clusters of β cells, thus forming artificial islets. Dr. Melton estimates that such implants would be about the size of a credit card.

The 2014 Boston biotech IPO boom

Meanwhile, the Boston area biotechnology community has seen a boom in young companies holding their initial public offerings (IPOs). 17 such companies were listed in a December 24 article in the Boston Business Journal. Among these companies are three that have been covered in the Biopharmconsortium Blog—Zafgen, Dicerna, and Sage Therapeutics.

We hope that 2015 will see at least the level of key discoveries, drug approvals, and financings seen in 2014.

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Source: Medical Progress Today 12/14/12 http://bit.ly/1sPO1WU

Source: Medical Progress Today 12/14/12 http://bit.ly/1sPO1WU

In our September 16, 2014 article on this blog, we announced the publication by Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports of a new book-length report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, by Allan B. Haberman, Ph.D.

As we said in that blog article, “cancer immunotherapy is a ‘hot’, fast-moving field”. Thus—inevitably—in the short time since the publication of our report, a great deal of late-breaking news has come in.

This article is a discussion of several key late-breaking news items, which were not published in the report.

Pricing of checkpoint inhibitor agents

As discussed in the report, two PD-1 inhibitors have been recently approved. Bristol-Myers Squibb (BMS)/Ono’s nivolumab was approved in Japan (where it is know by the brand name Opdivo) in July 2014 for treatment of unresectable melanoma. Pembrolizumab (Merck’s Keytruda) was approved in the U.S. for treatment of advanced melanoma on September 5, 2014. The very first checkpoint inhibitor to reach the market, the CTLA-4 inhibitor ipilimumab (Medarex/BMS’s Yervoy), was approved in the U.S. in 2011.

At the same time as the news of the approval of the PD-1 inhibitors nivolumab and pembrolizumab came out, information on the pricing of these agents also became available. However, because of the need to complete the report for publication, there was no time to discuss the issue of pricing adequately.

As discussed in a September 4, 2014 article in FiercePharma, the cost of nivolumab in Japan (according to the Wall Street Journal) is $143,000. According to the FierceBiotech article, this was greater than the introductory price for any other cancer drug, especially in Japan, where prices tend to be somewhat lower than in the U.S.

Meanwhile, as reported in a September 4, 2014 article in FierceBiotech, the cost of pembrolizumab in the U.S. will be $12,500 a month, or $150,000 a year.

For comparison, the launch price of BMS’ ipilimumab was $120,000. As we discussed in the report, the PD-1 inhibitors nivolumab and pembrolizumab—as seen in early clinical trials—appear to be more efficacious and have fewer adverse effects in treatment of melanoma.

As discussed in our report, checkpoint inhibitors such as ipilimumab, nivolumab and pembrolizumab are eventually likely to be used in combination with other drugs, including other immuno-oncology drugs, targeted therapies, and others. The price per month or per year of these potentially life-saving and at least in some cases curative combination therapies may thus be expected to go still higher. However, if cancers are pushed into long-term remission or even cure, then it might be possible to discontinue treatment with these expensive drug combinations. In such cases, the cost of treatment may even be less than current therapeutic regimens.

There are no analyses of the costs of specific immunotherapy drugs or cellular therapies in our report. However, we do discuss the issue of drug costs in the survey and interviews that are part of the report.

The issue of the costs of expensive drugs for life-threatening cancers is under discussion in the cancer community. For example, the American Society of Clinical Oncology (ASCO) has initiated an effort to rate oncology drugs not only on their efficacy and adverse effects, but also on their prices. ASCO’s concern is that pricing be related to the therapeutic value of drugs. And commentators such as Peter Bach, MD, MAPP (the Director of the Memorial Sloan Kettering Cancer Center’s Center for Health Policy and Outcomes) have been weighing in with their analyses. As additional immunotherapy drugs and cellular therapies reach the market, these discussions will certainly continue.

The Bristol-Myers Squibb-Merck lawsuit over PD-1 inhibitors

Another late-breaking news item that came out at the time of the publication of our report is the lawsuit between BMS and Merck over PD-1 inhibitors. Specifically, as soon as Merck gained FDA approval for pembrolizumab, BMS and its Japanese partner Ono sued Merck for patent infringement.

The patent in question is U.S. patent number 8,728,474. It was filed on December 2, 2010, granted to Ono on May 20, 2014, and licensed to BMS. The patent covers the use of anti-PD-1 antibodies to treat cancer. According to BMS and Ono’s claims, Merck started developing pembrolizumab after BMS and Ono had already filed their patent and were putting it into practice by developing their own PD-1 inhibitor, nivolumab.

The lawsuit asks for damages, and for a ruling that Merck is infringing the BMS/Ono PD-1 patent. Such a ruling may mean that BMS and Ono are owed royalties on sales of all rival PD-1 drugs, not just Merck’s. BMS/Ono and Merck are involved in parallel litigation in Europe.

Merck acknowledges Ono’s method patent, but says that it is invalid. Merck also said the lawsuit will not interfere with the U.S. launch of pembrolizumab.

We shall have to watch the proceedings in the U.S. District Court for the District of Delaware to see the outcome of this case. Although this lawsuit was not discussed in our report, the report does include a discussion of the fierce race between PD-1 inhibitor developers Merck and BMS to be the first to market, and to gain the largest market share. The lawsuit is clearly one element in this race.

Merck Serono discontinues development of the cancer vaccine tecemotide

On September 18, 2014, Merck KGaA (Darmstadt, Germany; also known as Merck Serono and EMD Serono) announced that it has discontinued development of the cancer vaccine tecemotide. Tecemotide is a peptide vaccine that was formerly known as Stimuvax. It was originally developed by Oncothyreon (Seattle, WA) and licensed to Merck Serono in 2007.

We covered tecemotide in our report, both as an example of a cancer vaccine that had failed in Phase 3 clinical trials, and as an example of a vaccine that was nevertheless still under development. As discussed in our report, in a Phase 3 trial known as START in non-small cell lung cancer (NSCLC) patients, researchers found no significant difference in overall survival between administration of tecemotide or placebo. However, a subsequent analysis suggested that there was a statistically significant survival advantage for tecemotide compared with placebo in a pre-defined subset of patients. Based on these results, Merck Serono began a second Phase 3 trial in that subset.

However, as the result of a failure in a Phase 3 trial in Japan sponsored by Oncothyreon (reported on August 19, 2014), Merck Serono decided to discontinue development.

As stated by Merck Serono’s Executive Vice President and Global Head of R&D Luciano Rossetti, “While the data from the exploratory subgroup analysis in the START trial generated a reasonable hypothesis to warrant additional study, the results of the recent trial in Japanese patients decreased the probability of current studies to reach their goals.”

As we discussed in our report, the cancer vaccine field has been rife with clinical failures—from its beginnings in the 1990s to the present day. This has especially included late-stage failures, not only that of Merck Serono’s tecemotide, but also, for example, GlaxoSmithKline’s (GSKs) MAGE-A3 vaccine. Only one anticancer vaccine—sipuleucel-T (Dendreon’s Provenge) for treatment of metastatic castration-resistant prostate cancer—has ever reached the market, and its therapeutic effects appear to be minimal.

Despite these poor results, researchers and companies persist in their efforts to develop cancer vaccines. Our report discusses why cancer vaccine R&D continues despite the overwhelming history of failure, the hypothesized reasons for these failures, and what researchers and companies can do and are doing to attempt to obtain better results.


As a fast-moving, important field, cancer immunotherapy will continue to generate scientific, medical, and market news. There will continue to be periodic meetings, such as the 2014 European Society for Medical Oncology (EMSO) meeting (September 26-30, Madrid, Spain), in which positive results of small, early-stage trials of several checkpoint inhibitors were presented. Our report—an in-depth discussion of cancer immunotherapy—can enable you to understand such future developments, as well as current ones. It is also designed to inform the decisions of leaders in companies and in academia that are involved in cancer R&D and treatment.

For more information on Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, or to order it, see the Insight Pharma Reports website.


As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to your company, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.