CAR T cells attacking a cancer cell. (Source: National Cancer Institute)

On May 3, 2017 Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of a new book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes, by Allan B. Haberman, Ph.D.

The new 2017 report includes an updated discussion of approved and clinical stage agents in immuno-oncology. It also addresses the means by which researchers and companies are attempting to build on prior achievements in immuno-oncology to achieve improved outcomes for more patients. This approach is often referred to as “immuno-oncology 2.0.” The American Society of Clinical Oncology (ASCO) named “immunotherapy 2.0” as its “Advance of the Year” for 2017.

As discussed in the report, researchers have found that checkpoint inhibitors such as pembrolizumab (Merck’s Keytruda) and nivolumab (Bristol-Myers Squibb’s Opdivo) produce tumor responses by reactivating TILs (tumor infiltrating lymphocytes). As a result, they have been developing biomarkers that distinguish inflamed (i.e. TIL-containing) tumors—which are susceptible to checkpoint inhibitor therapy—from “cold” tumors, which are not. They have also been working to develop means to render “cold” tumors inflamed, via treatment with various conventional therapies and/or development of novel agents. These studies constitute the major theme of immuno-oncology 2.0.

Meanwhile, cellular immunotherapy has also been advancing, with two chimeric antigen receptor (CAR) T-cell therapies (from Novartis and Kite Pharma) in preregistration with the FDA as of March 2017.

These and other areas of current cancer immunotherapy R&D are discussed in the new report.

The first wave of immuno-oncology 2.0 treatments has begun to achieve regulatory approval:

  • On May 12, 2017, Merck gained FDA approval to market a combination of pembrolizumab with chemotherapy (specifically, carboplatin plus pemetrexed) for first-line treatment of non-small cell lung cancer (NSCLC). This is based on a Phase 2 clinical study that showed that the chemo/pembrolizumab combination resulted in a much higher statistically-significant overall response than chemo alone — 55% vs. 29%. As we discuss in our report, certain types of chemotherapy can induce immune responses that convert “cold” tumors into inflamed tumors, thus making them susceptible to checkpoint inhibitor treatment.
  • On May 23, 2017, the FDA awarded accelerated approval to Merck’s pembrolizumab for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that exhibit high microsatellite instability (MSI-H) or are mismatch repair deficient (dMMR). This indication includes patients with solid tumors that have progressed following prior treatment, and who have no satisfactory alternative treatment options. It also includes patients with colorectal cancer that has progressed following treatment with chemotherapy. This is the first approval of an anticancer agent based on a tumor’s biomarker, regardless of where the tumor originated in the body. As we discuss in our report, mismatch-repair deficiency results in a large somatic mutation load. This supports a large and diverse population of TILs, which are specific for mutation-associated neoantigens. Treatment with checkpoint inhibitors may reactivate these TILs, resulting in effective antitumor immune responses.

Our report is designed to enable readers to understand current and future developments in immuno-oncology, especially including new developments in immunotherapy 2.0. It is also designed to inform the decisions of leaders in companies and in academic groups that are working in areas that relate to cancer R&D and treatment.

For more information on the report, 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.

Adenosine Deaminase

Adenosine Deaminase

Our recent book-length report, Gene Therapy: Moving Toward Commercialization was published by Cambridge Healthtech Institute in November 2015. As indicated by its title, the report focuses on clinical-stage gene therapy programs that are aimed at commercialization, and the companies that are carrying out these programs.

Until recently, gene therapy was thought of as a scientifically-premature field with little prospect of near-term commercialization. However, as outlined in our report, numerous companies have been pursuing clinical programs aimed at regulatory approval and commercialization. These efforts have attracted the interest of investors and of large pharma and biotech companies. As a result, several gene therapy specialty companies have gone public, and some companies in this sector have attracted large pharma or biotech partnerships.

A key question addressed in our report is whether any gene therapies might be expected to reach the U.S. and/or European markets in the near term. In the last chapter (Chapter 9) of the report, we included a table (Table 9.1) of eight gene therapy products that we deemed to be likely to reach the market before 2020.

One of these products, uniQure/Chiesi’s Glybera (alipogene tiparvovec), a treatment for the ultra-rare condition lipoprotein lipase deficiency (LPLD), was approved in Europe in 2012. It is thus the “first commercially available gene therapy” in a regulated market. However, uniQure has dropped plans to seek FDA approval for Glybera.

As we discussed in our December 17, 2015 article on this blog, another product listed in Table 9.1, Spark Therapeutics’ SPK-RPE65, is expected to reach the U.S. market by 2017. SPK-RPE65 is a gene therapy for the rare retinal diseases Leber congenital amaurosis and retinitis pigmentosa type 20. As of March 9, 2016, Spark is preparing to file a Biologics License Application (BLA) for SPK-RPE65 in the second half of 2016. SPK-RPE65 may be the first gene therapy approved in the U.S. Spark also plans to file a marketing authorization application (MAA) in Europe in early 2017.

Now comes an announcement of the impending European marketing of a third product listed in Table 9.1, GlaxoSmithKline/San Raffaele Telethon Institute for Gene Therapy (TIGET)’s GSK2696273, now called Strimvelis. On April 1, 2016, the The European Medicines Agency (EMA) recommended the approval of Strimvelis in Europe, for the treatment of children with ADA severe combined immune deficiency (ADA-SCID) for whom no matching bone marrow donor is available. ADA-SCID is a type of SCID caused by mutations in the gene for adenosine deaminase (ADA).

Approximately 15 children per year are born in Europe with ADA-SCID, which leaves them unable to make certain white blood cell that are involved in the immune system. ADA-SCID is an autosomal recessive condition that accounts for about 15% of cases of SCID. ADA deficiency results in the intracellular buildup of toxic metabolites that are especially deleterious to the highly metabolically active T and B cells. These cells thus fail to mature, resulting in life-threatening immune deficiency. Children with ADA-SCID rarely survive beyond two years unless their immune function is rescued via bone marrow transplant from a compatible donor. Thus Strimvelis is indicated for children for whom no compatible donor is available.

As we discussed in our report, the development of therapies for ADA-SCID goes back to the earliest days of gene therapy, in 1990. Interestingly, Strimvelis (GSK2696273) is based on a Moloney murine leukemia virus (MoMuLV) gammaretrovirus vector carrying a functional gene for ADA. In other applications (for example, gene therapy for another type of SCID called SCID-X1), the use of MoMuLV vectors resulted in a high level of leukemia induction. As a result, researchers have developed other types of retroviral vectors (such as those based on  lentiviruses) that do not have this issue. Nevertheless, Strimvelis Mo-MuLV-ADA gene therapy has been show to be safe over 13 years of clinical testing, with no leukemia induction. As discussed in our report, researchers hypothesize that ADA deficiency may create an unfavorable environment for leukemogenesis.

Delivery of Strimvelis requires the isolation of hematopoietic stem cells (HSCs) from each patient, followed by ex vivo infection of the cells with the MoMuLV-ADA construct. The transformed cells are then infused into the patient, resulting in restoration of a functional immune system.

With the EMA recommendation of approval for Strimvelis, it is expected that the therapy will be approved by the European Commission approval in July 2016.

Strimvelis is the result of a 2010 partnership between GSK and Italy’s San Raffaele Telethon Institute for Gene Therapy (TIGET), and the biotechnology company MolMed, which is based at TIGET in Milan. MolMed is currently the only approved site in the world for production of and ex vivo therapy with Strimvelis. However, GSK is looking into ways of expanding the numbers of sites that will be capable of and approved for administration of the therapy. GSK’s plans will include seeking FDA approval for expansion into the U.S. market.

Moreover, as discussed in our report, under the GSK/TIGET agreement,  GSK has exclusive options to develop six further applications of ex vivo stem cell therapy, using gene transfer technology developed at TIGET. GSK has already exercised its option to develop two further programs in two other rare diseases. Both are currently in clinical trials. Because of the issue of leukemogenesis with most gammaretrovirus-based gene therapies, these other gene therapy products are based on the use of lentiviral vectors.

Given the tiny size of the market for each of these therapies, pricing is an important—and tricky—issue. For example, treatment with UniQure’s Glybera, as of 2014, cost $1 million. As of now, GSK is not putting a price on Stremvelis, but reportedly the therapy will cost “very significantly less than $1 million” if and when it is approved.


The success of researchers and companies in moving three of the eight gene therapies listed in Table 9.1 toward regulatory approval suggests that gene therapy will attain at least some degree of near term commercial success. However, Glybera and Strimvelis are for ultra-rare diseases, and are thus not expected to command large markets.

However, as discussed in our previous blog article, SPK-RPE65 may achieve peak sales ranging from $350 million to $900 million. And as discussed in our report, some of the remaining therapies listed in Table 9.1, especially those involved in treatment of blood diseases or cancer, may achieve sales in the billions of dollars. Thus, depending on the timing and success of clinical trials and regulatory submissions of these therapies, gene therapy may demonstrate a degree of near-term commercial success that few thought was possible just five years ago.

Meanwhile, even therapies that address rare or ultra-rare diseases will be expected to save the lives or the sight of patients who receive these products.


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.

Baby_Face Source:

Baby_Face Source:

In November 2015, the use of gene editing technology to treat an 11-month-old child with leukemia was reported in news articles in Nature and in Science. Because of the human-interest value of this story, it was also reported in Time magazine and in the New York Times.

Data from this first-in-humans clinical use of the therapy will be presented at the 57th American Society of Hematology (ASH) Annual Meeting in Orlando, FL in early December 2015.

The young patient was treated with a complex cellular immunotherapy regimen developed by Cellectis (Paris, France and New York, NY). Cellectis’ platform involves production of allogeneic (rather than autologous) chimeric antigen receptor (CAR) T-cells to create an “off-the-shelf solution” to cellular immunotherapy for cancer, potentially simplifying manufacturing and standardization of therapies.

We have discussed CAR T-cell therapies on this blog, and—in more detail—in two book-length reports published by Cambridge Healthtech Institute (CHI). These are our 2014 Cancer Immunotherapy report, and our new November 2015 report, Gene Therapy: Moving Toward Commercialization.

CAR T-cell therapies directed against the B-cell antigen CD19, being developed by Novartis/University of Pennsylvania, Juno Therapeutics, and Kite Pharma, have demonstrated impressive clinical results against B-cell leukemias and lymphomas. However, in order to avoid immune incompatibility, CAR T-cell must be constructed and manufactured using autologous T-cells derived from the patient to be treated. This is an expensive and laborious process. Hence the rationale for allogeneic CAR T-cell therapy.

Cellectis uses gene editing in construction of its allogeneic CAR T-cells. Specifically, the company first modifies T-cells from healthy donors with an anti-CD19 CAR gene construct, similar to the methods used by other companies that are developing anti-CD19 CAR cellular immunotherapies. Cellectis then uses gene editing based on transcription activator-like effector nucleases (TALENS) to disrupt expression of the T-cells’ TCR (T-cell receptor) genes. It is the TCRs of the transplanted T cells that recognize the patient’s own cells as foreign, and thus attack them. Cellectis also uses TALENS gene editing to disrupt expression of a gene for another cell-surface protein, CD52. CD52 is present on mature lymphocytes, and is the target of the monoclonal antibody drug alemtuzumab (Genzyme’s Lemtrada). Researchers can then use alemtuzumab to prevent host-mediated rejection of the HLA mismatched CAR19 T cells. Cellectis’ “Talen engineered universal CAR19 T cells” can thus in principle be used to treat any patient with B-ALL (B-cell acute lymphoblastic leukemia), instead of autologous anti-CD19 CAR T-cells.

The treatment of the young patient, Layla Richards of London, was on a compassionate use basis. She had refractory relapsed B-ALL, and was expected to die shortly. Meanwhile, Cellectis had a universal CAR19 (UCART19) cell bank in the same hospital in which Layla was being treated. The cell bank had been characterized in detail, in preparation for submission for regulatory approval and Phase 1 testing.

Prior to administration of the UCART19 cells, the patient received lymphodepleting chemotherapy (including administration of alemtuzumab). After getting the UCART19 cells in June 2015 (near her first birthday), Layla went into remission, and has no trace of leukemia. After about three months she had a bone marrow transplant to help her immune system recover, and is now at home. However the follow-up period since her treatment has only been 5 months. Therefore, Layla’s doctors do not yet know how durable the remission will be. The key question is how long the UCART19 cells can survive in the body and prevent recurrence of leukemia.

Gene editing companies and their technologies discussed in our November 2015 report

Our November 2015 gene therapy report includes a chapter (Chapter 8) that focuses on gene-editing technologies and on companies that are developing therapies based on these technologies. The gene-editing technology that has been getting the most attention from the scientific and financial communities is known as CRISPR/Cas9. The other two technologies discussed in Chapter 8 are TALENS and zinc-finger nucleases (ZFN). The basic principle of these gene-editing technologies is that a “molecular scissors” makes a specific double-strand break in a deleterious DNA sequence. This break is either repaired in such a way as to disrupt the gene by forming deletions or mutations, or—if a suitable donor DNA is provided—the deleterious gene is replaced with a desired, functional gene sequence.

Gene-editing specialty companies discussed in our report based on CRISPR/Cas9 technology include Editas Medicine (Cambridge, MA) (which also utilizes TALENS), Intellia Therapeutics (Cambridge MA), CRISPR Therapeutics (Basel, Switzerland; Stevenage, U.K.; and Cambridge MA), and Caribou Biosciences (Berkeley, CA). Sangamo BioSciences (Richmond, CA), which is also discussed in our report, is a pioneer in ZFN technology.

Despite the predominant focus on CRISPR/Cas9 technology and companies in the biotechnology and venture capital communities, the first clinical studies involving gene editing have used Sangamo’s ZFN technology. These studies are in the field of HIV/AIDS. They involve ex vivo treatment of HIV-infected patients’ T-cells with a specific ZFN-based vector, in order to render the patients resistant to further manifestations of the disease.

Meanwhile, Editas has developed a vector designed to enable the company to move its CRISPR/Cas9 technology into the clinic. Editas’ first clinical program will be a potential treatment for a form of the genetically-driven retinal disease, Leber congenital amaurosis (LCA). (This is a different form of LCA than the one being targeted by Spark Therapeutics, which we discussed in our November 16, 2015 article on this blog).

bluebird bio (Cambridge, MA) is also pursuing a gene-editing technology program based on homing endonucleases and MegaTAL enzymes. This research and preclinical-stage program came to bluebird via its 2014 acquisition of Precision Genome Engineering Inc. (Seattle WA).

Cellectis is not the only company that is combining CAR T-cell therapies with gene-editing technology. In May 2015, Editas formed a collaboration with Juno Therapeutics to pursue research programs that combine Editas’ genome editing technologies with Juno’s CAR and TCR T-cell technologies.


Despite the great deal of excitement about gene-editing technologies and companies (especially CRISPR/Cas9) these are early days for development of therapies based on these technologies. Despite the almost miraculous results in the treatment of Layla Richards, it is only one case, and the follow-up period has been short. Nevertheless, this one case may open the way for this therapy to be used in other “desperate situations” where there is no time, or it is not possible, to use a patient’s own T cells. And researchers are already speculating that a similar technique may be used to treat people with other blood cancers, and eventually people with solid tumors.

For more information on our November 2105 gene therapy report, 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.

OX40 Protein Source: Emw

OX40 Protein Source: Emw

Haberman Associates has a new website, with the same URL as previously but with many improvements. This article is the first Biopharmconsortium Blog post to be posted after the new website has gone online. Please explore the new site, and send any comments on the site to us.

In addition to announcing our new website, this article is designed to outline several new areas of cancer immunotherapy R&D.

Research and development of novel checkpoint inhibitors for cancer immunotherapy

Our September 2014 book-length Insight Pharma Report, “Cancer Immunotherapy: immune checkpoint inhibitors, cancer vaccines, and adoptive T-cell therapies” focused on agents that had reached the clinic. In the case of checkpoint inhibitors, the report did not cover the universe of immune checkpoints, but only those that have been addressed with late-stage agents, some of which had entered—or were about to enter—the market. However, as we stated in the report, researchers expect new experimental products to emerge from immune checkpoint research in the next 5-10 years.

In the report, we mentioned research on agents to target the lymphocyte-activation gene 3 (LAG-3, CD223) pathway. In a published study in mice, Bristol-Myers Squibb (BMS) researchers and their academic collaborators obtained evidence that dual treatment with an anti-PD-1 (such as BMS’ nivolumab) and an anti-LAG-3 monoclonal antibody (MAb) cured most mice of established tumors that were largely resistant to single antibody treatment. They concluded that dual blockade of PD-1 and LAG-3 might constitute a viable strategy for cancer immunotherapy, which might be superior to blocking PD-1 alone.

At the time of our report’s publication, BMS had initiated two Phase 1 safety studies with an investigational anti-LAG-3 MAb. These are a study of anti-LAG-3 with and without anti-PD-1 in treatment of solid tumors (clinical trial number NCT01968109), and a study of anti-LAG-3 in relapsed or refractory chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) (clinical trial number NCT02061761). Both of these studies are still ongoing and recruiting patients.

Another checkpoint inhibitor target that is begin investigated (in preclinical studies) for potential use in cancer immunotherapy is TIM-3 (T-cell immunoglobulin domain and mucin domain 3). TIM-3 is is co-expressed on PD-1+ CD8 T cells in mouse models with solid tumors or hematologic malignancies. In a preclinical mouse melanoma model, combined blockade of TIM-3 and PD-1, or TIM-3 and CTLA4, was more effective in prolonging survival than blocking either protein alone. Moreover, the combination of anti-CTLA4, anti-TIM-3 and anti-LAG-3 produced further suppression of growth of the melanoma tumor. These data suggest that blockade of multiple inhibitory receptors—including TIM-3 and LAG-3—results in synergistic antitumor activity.

Research and development of agonist antibodies for use in cancer immunotherapy

Another approach to antibody-based cancer immunotherapy—in addition to targeting checkpoint inhibitors—is development of agonist antibodies. This is the subject of an upcoming conference in Boston—sponsored by Cambridge Healthtech Institute (CHI), on May 7-8, 2015. This conference is part of CHI’s annual PEGS Boston (Essential Protein Engineering Summit). Agonist antibodies target certain cell surface proteins on T cells, resulting in stimulation of the activity of the T cells. This contrasts with checkpoint inhibitors, which are designed to overcome blockages to T cell activity mediated by immune checkpoints.

Among the targets for agonist antibodies are two members of the tumor necrosis receptor (TNFR) superfamily—CD27 and OX40.

Celldex Therapeutics’ fully-human monoclonal antibody (MAb) agent varlilumab (CDX-1127) targets CD27. As discussed in our cancer immunotherapy report, activation of naïve T-cells requires both T-cell receptor (TCR) signaling and costimulation by a “second signal”. In our report, we used the example of CD28 (present on the surface of T cells) interacting with B7 [present of the surface of an antigen-presenting cell (APC) such as a dendritic cell] to deliver a “second signal”. CD27 is a member of the CD28 superfamily, and it interacts with CD70 to deliver a “second signal”. Varlilumab can substitute for CD70, and deliver a costimulatory signal to T cells whose TCRs are engaged. This can change a weak immune response into a strong, prolonged response. In preclinical models, immunostimuation by varlilumab has been shown to mediate antitumor effects.

In addition to the immunostimulatory activity of varlilumab, this agent may also exert direct therapeutic effects against tumors that express CD27 at high levels, such as human B and T cell lymphomas. Varlilumab has shown potent anti-tumor activity against these lymphomas in preclinical models. In these models, varlilumab may exert its therapeutic activity both via “second-signal” immune activation, and via direct antitumor activity against CD27-bearing lymphoma cells.

Varlilumab is now in ongoing Phase 1 clinical trials against solid and hematological tumors (clinical trial number NCT01460134), and in ongoing Phase 1 and Phase 2 trials in combination with the anti-PD-1 MAb agent nivolumab (BMS’ Opdivo) against advanced refractory solid tumors (clinical trial number NCT02335918). Reports of interim data from clinical trials of varlilumab at scientific meetings in 2013 and in 2014 indicate that this agent was very well tolerated and demonstrated biological activity and signs of clinical activity against advanced, treatment-refractory lymphoid malignancies and metastatic melanoma and renal cell carcinoma.

On March 17, 2015 Celldex announced that it had entered into an agreement with Roche to evaluate the safety, tolerability and preliminary efficacy of varlilumab in combination with Genentech/Roche’s investigational anti-PDL1 agent MPDL3280A in a Phase 1/2 study in renal cell carcinoma. This is based on preclinical studies that suggest that the combination of these two agents may be synergistic, and enhance anti-tumor immune response as compared to either agent alone. In Celldex’s Phase 1 study of varlilumab in multiple solid tumors, promising signs of clinical activity had been seen in patients with refractory renal cell carcinoma. This included a durable partial response (11.0+ months) with decreases in tumor volume over time, and 4 patients with stable disease over periods ranging from 5.3 to 30.7+ months.

Another target for agonist MAbs in immuno-oncology is OX40. MedImmune (the global biologics R&D arm of AstraZeneca) is testing the OX40 agonist MAb MEDI6383 in an ongoing Phase 1 clinical trial (clinical trial number NCT02221960) against recurrent or metastatic solid tumors. MedImmune’s OX40 program is based on technology developed by AgonOx (Portland, OR). The two companies entered into an exclusive global partnership to develop OX40 agonists in 2011.

OX40 is a costimulatory receptor that can potentiate TCR signaling in T cells, leading to the activation of these cells by antigens recognized by their TCRs. Engagement of OX40 by its natural ligands on dendritic cells, or by anti-OX40 antibodies initiates a signal transduction cascade that enhances T cell survival, proliferation, and cytokine production, and can augment immune responses to tumors. Preclinical studies have shown that OX40 agonist antibodies increase antitumor immunity and improve tumor-free survival. A Phase 1 clinical study of an mouse anti-OX40 agonist MAb in patients with advanced cancer was carried out by researchers at the Providence Portland Medical Center in Portland, OR. (AgonOx is a spin-off of the Providence Portland Medical Center.) The study (clinical trial number NCT01644968), whose results were published in 2013, found that treatment with one course of the anti-OX40 MAb induced regression of at least one tumor metastasis in 12 of 30 patients, and exhibited an acceptable toxicity profile. Treatment with the agent also increased the antitumor reactivity of T and B cells in patients with melanoma.

In the upcoming CHI agonist antibody conference, Scott A. Hammond, Ph.D., Principal Scientist, Oncology Research at MedImmune will discuss the preclinical characterization of MedImmune’s OX40 agonists now in clinical trials.


The studies on novel immune checkpoint inhibitors and agonist antibodies illustrate that researchers are continuing to advance the frontiers of immuno-oncology beyond the late-stage MAb agents described in our report. Moreover, many of these studies involve clinical trials of combination therapies of the novel agents with other therapeutics discussed extensively in our report, including the CTLA-4 inhibitor ipilimumab (Medarex/BMS’s Yervoy), the PD-1 inhibitors nivolumab (BMS’ Opdivo) and pembrolizumab (Merck’s Keytruda), and the PD-L1 inhibitor MPDL3280A (Genentech/Roche). This is consistent with the idea that “the future of cancer immunotherapy is combination therapy”. In the survey that Insight Pharma Reports conducted in conjunction with our report, 80% of respondents agreed with this statement.

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.