CAR-T procedures
Source: National Cancer Institite

Late stage cellular immunotherapy products for treatment of hematologic tumors

In the field of commercialization of cellular immunotherapy for cancer, all eyes have been on two chimeric antigen receptor (CAR) T-cell therapies (from Novartis and Kite Pharma), which have been in preregistration with the FDA as of March 2017. We discussed the field of CAR-T cell therapies—as well as other cellular immunotherapies for cancer—in Chapter 6 of our recently published book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes

Both the Novartis therapy, CTL019 (tisagenlecleucel-T), and the Kite therapy, KTE-C19 (axicabtagene ciloleucel) target CD19, which is a cell surface protein that is expressed on all malignant and normal B-cells.

On July 13, 2017, Novartis announced  that FDA’s Oncologic Drugs Advisory Committee (ODAC) had unanimously recommended approval of CTL019 for the treatment of relapsed or refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). The ODAC recommendation is based on review of Novartis’ CTL019 r/r B-cell ALL development program, including the ELIANA study (NCT02435849). ELIANA is the first pediatric global CAR-T cell therapy registration trial. Findings from other clinical trials in the U.S. also supported the recommendation and the Biologics License Application (BLA) for CTL019.

On August 30, 2017 the FDA approved Novartis’ CTL019—now known as Kymriah (tisagenlecleucel)—for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. Novartis’ Kymriah is thus the first-ever commercially approved CAR-T cell therapy to reach the market. However, Kite’s KTE-C19 is close on Novartis’ heels.

On August 28, 2017, Kite and Gilead announced that the two companies have entered into a definitive agreement pursuant to which Gilead will acquire Kite for $11.9 billion. Via this acquisition, Gilead “instantly” becomes a leader in cellular immunotherapy for cancer, going head-to-head with Novartis.

On October 18, 2017, Kite and Gilead announced that the FDA had approved Kite’s Yescarta (axicabtagene ciloleucel, also known as axi-cel), for the treatment of adults with relapsed or refractory large B-cell lymphoma, including aggressive non-Hodgkin lymphoma, who have failed two or more traditional treatments. Yescarta was approved about six weeks earlier than expected.

Other CAR-T based immunotherapies for treatment of hematologic tumors

As discussed in our report, there is also a third company, Juno Therapeutics, that was in the race to develop CD19-targeting CAR-T-based cellular immunotherapies for regulatory approval in 2017. However, Juno’s lead product, JCAR015, suffered a series of toxicity-related setbacks. Juno thus abandoned both JCAR015 and the race for 2017 approval. It is now focusing on development of another CD19-targeting CAR-T product, JCAR017. This therapy is directed towards treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

JCAR017 demonstrated promising efficacy results in a Phase 1 trial known as TRANSCEND. Adverse results were generally mild, and could be resolved with treatment. [ The company presented the results of the TRANSCEND trial at the 2017 American Society for Clinical Oncology (ASCO) annual meeting in early June.]

Juno expects to begin a pivotal trial of JCAR017 this year in DLBCL. JCAR017 received a breakthrough therapy designation from the FDA for non-Hodgkin lymphoma in December 2016.

As we also discuss in our report, another CAR-T therapy directed against a hematologic malignancy, bluebird bio’s bb2121, is under development in collaboration with Celgene. bb2121 targets B-cell maturation antigen (BCMA), and is directed toward treatment of multiple myeloma (MM). bluebird and Celgene announced the results of an ongoing first-in-human open-label Phase 1 multicenter clinical study of bb2121 in 18 patients with relapsed/refractory MM at the 2017 ASCO Annual Meeting on June 5, 2017. bb2121 demonstrated promising efficacy results in this study, and no dose-limiting toxicities were observed. No patient in the active dose cohorts has had disease progression. The researchers thus plan on initiating the expansion phase of the study in the coming months of 2017.

Can researchers develop cellular immunotherapy for solid tumors?

As various companies work to move CAR T-cell therapies that target tumor antigens other than CD19 into the clinic, a particularly important question is whether CAR T-cell technology might be used to target solid tumors. Our report  discusses several clinical-stage products designed to target various types of solid tumors. These include products in three categories—tumor-infiltrating lymphocytes (TILs), CAR T-cells, and recombinant T-cell receptor (TCR) cells. Researchers developing such therapies (especially CAR T-cell therapies) recognize the special difficulty in targeting solid tumors, and are including studies attempting to determine the barriers that might prevent effective therapy of solid tumors with their experimental therapies. Some companies have also been producing therapies that are designed to overcome these barriers.

Now comes a “Brief Report” (published in December 2016) in the New England Journal of Medicine that focuses on an experimental treatment for the brain cancer glioblastoma with CAR T-cells. The study was carried out by researchers at the City of Hope (Duarte, CA). In this study, the CAR T-cells used were designed to target the high-affinity interleukin-13 (IL-13) receptor IL13Rα2, which is overexpressed in a majority of glioblastomas. The researchers administered the therapy locally in the brain, by injecting it into the tumor site and/or via infusion in the brain’s ventricular system. This contrasts with the use of CAR T-cells for treatment of hematological malignancies, in which the CAR T-cells are administered systemically.

Treatment with the CAR T-cells induced a transient, complete response in a patient with recurrent multifocal glioblastoma. This included a dramatic improvement in quality of life, including the discontinuation of use of systemic glucocorticoids and a return to normal life activities. The remission was sustained for 7.5 months. Nevertheless, the patient eventually developed new tumors. The authors concluded that their study provides proof-of-principle data that confirm IL13Rα2 as a useful immunotherapeutic target in glioblastoma, and suggest that CAR T cells can mediate profound antitumor activity against a difficult-to-treat solid tumor.

Meanwhile, as discussed in our report, researchers at Kite Pharma and University of Pennsylvania/ Novartis have been studying treatment of glioblastoma with CAR T-cells that target the epidermal growth factor receptor variant III (EGFRvIII). Some 20-30% of glioblastomas express this variant. The two groups are running parallel early-stage clinical trials of two different EGFRvIII CAR agents. The researchers believe that these parallel studies may be informative for future development of CAR therapies for solid tumors. However, no dramatic results such as seen by the City of Hope group have yet been reported for these studies.

TIL therapies for solid tumor cancers

Currently, the most successful cellular immunotherapies for solid tumor cancers have involved treatment with TILs. Steven A. Rosenberg, M.D., Ph.D., of the National Cancer Institute pioneered the study of TIL therapy, and of cellular immunotherapy in general. Our 2017 report  includes extensive discussions of the studies of TIL therapy carried out by Dr. Rosenberg and his collaborators, from the 1980s to today. Unlike CAR T-cell and recombinant TCR-based therapies, TILs are normal T cells that have not been genetically engineered.

Most clinical studies with TIL therapy have been in advanced melanoma. However, more recent studies have included “proof of principle” studies in patients with epithelial cancers of the digestive system. In some cases, these have included studies with TILs that target cancers with the KRAS G12D mutation, a notorious “undruggable” driver mutation that is involved in causation of many human cancers. More recent work in Dr. Rosenberg’s group has included mechanistic studies designed to determine the neoantigens that are targeted by antitumor TILs. Some of these most recent studies are being applied to treatment of non-small cell lung cancer (NSCLC).

However, as discussed in our report and in another article on this blog , TIL therapies have been difficult to commercialize. Nevertheless, in recent years, a San Carlos, CA company called Lion Biotechnologies (which on June 27, 2017 changed its name to Iovance Biotherapeutics has been focusing on doing just that. Iovance has been working with Dr. Rosenberg and his colleagues at the NCI under a Cooperative Research and Development Agreement (CRADA) to develop and commercialize TIL therapies.

On June 5, 2017, Iovance announced a poster presentation  of a study of 16 patients enrolled in the first cohort of its ongoing Phase 2 study of LN-144 for the treatment of metastatic melanoma, at the ASCO Annual Meeting.   LN-144 is the company’s autologous TIL therapy for the treatment of patients with refractory metastatic melanoma. Iovance’s Phase 2 clinical trial of LN-144 (clinical trial number NCT02360579) is designed to assess the safety, efficacy, and feasibility of the autologous TIL therapy, followed by interleukin-2 (IL-2), in the treatment of this class of patients.

The data presented at the ASCO meeting showed that Iovance can manufacture TILs at its central GMP facilities to treat patients at multiple clinical sites. According to the company, the initial data show clinically-meaningful outcomes, as assessed both by objective response rate (ORR) and disease control rate (DCR), in a heavily pre-treated patient group, all of whom had received prior anti-PD-1 (e.g., pembrolizumab or nivolumab) and over 80% with prior anti-CTLA-4 (e.g., ipilimumab) checkpoint inhibitors.

In the ASCO poster presentation, the company’s academic collaborators presented updated data from 16 patients who were infused as of April 24, 2017. These advanced metastatic melanoma patients were a median age of 55 and were highly refractory to multiple prior lines of therapy with significant tumor burden at baseline. Of the evaluable patients, a 29% ORR was reported, including one complete response (CR) continuing beyond 15 months post-administration of a single TIL treatment. 77% percent of patients had reduction in target tumor size. The mean time to first response was 1.6 months, with the CR developing at 6 months.

Responses were observed in patients with wild type tumors and with tumors carrying BRAF  mutations. The protocol for this study was amended to increase the sample size for the study, as well as to further define the patient population to patients with unresectable or metastatic melanoma who have progressed after immune checkpoint inhibition therapy, and if BRAF mutation-positive, after BRAF targeted therapy.

In addition to the melanoma study, Iovance plans to initiate Phase 2 TIL therapy studies in cervical and head-and-neck cancers during 2017. The TIL populations to be used for these studies, LN-145, will be selected for reactivity to human papillomavirus (HPV) proteins E6 and E7. The selection and use of such TIL populations was developed by researchers in Dr. Rosenberg’s group. Iovance is currently enrolling patients in its Phase 2 melanoma and cervical and head-and-neck cancer studies.

Recent review on treating solid tumors with CAR-T cell therapies

Now comes a review by Irene Scarfò, Ph.D. and Marcela V. Maus, MD, Ph.D. published in March 2017 in the Journal for ImmunoTherapy of Cancer. This review focuses on factors that may limit the efficacy of CAR-T cell therapies in solid tumors, and how these factors might be overcome.

Some of the factors discussed in this review include:

• Hypoxia, nutrient starvation, and resulting changes in T-cell metabolism (many human solid tumors contain high percentages of hypoxic tissue)
• Interactions between CAR T-cells and tumor stroma that may inhibit the ability of CAR T-cells to penetrate tumors
• Targeting cytokine networks, for example by inducing the local release of cytokines that promote anti-tumor immune responses. For example, interleukin-12 (IL-12) is a key inflammatory cytokine, which is able to induce several pathways that promote such a response. (We discussed IL-12-based therapeutics for use in immuno-oncology, as well as therapeutics based on such cytokines as IL-2, IL-10 and IL-15, in Chapter 1 of our report.) Starting from these considerations, several groups are investigating so-called “fourth generation” CAR T-cells, which are CAR-T cells that are designed to secrete IL-12.

The immunosuppressive environment of the interior of solid tumors results in the upregulation of surface inhibitory receptors, especially programmed death-1 (PD-1) on CAR T-cells. PD-1 inhibits the antitumor activity of the CAR T-cells. Researchers are therefore developing therapies in which they treat solid tumors with a combination of CAR T-cells directed to an appropriate tumor antigen and an immune checkpoint inhibitor such as pembrolizumab or nivolumab. Alternatively, researchers may use a genetic engineering strategy to block PD-1.

Currently, researchers are testing approaches based on these factors in animal models, and may soon be advancing into human clinical trials. As with other approaches classified as “immuno-oncology 2.0”, these trials will involve the use of combination therapies. The goal of early clinical trials in this area will be to determine the safest and most effective combinations for treatment of patients with solid tumors.

Conclusions

The field of cellular immunotherapy for cancer is an increasingly exciting and fast-moving area. Most of the focus is on breakthrough treatments of CD19+ hematologic tumors, with late-stage CAR T-cell therapies such as Novartis’ CTL019 (tisagenlecleucel-T), and Kite’s KTE-C19 (axicabtagene ciloleucel), which are rapidly approaching the market. However, there are also new indications that researchers and companies might be able to develop cellular immunotherapy-based treatments for certain types of solid tumors in the next several years. All in all, cellular immunotherapy will be an increasing area of focus for researchers, companies, and analysts over the remainder of this decade and beyond.

For more information on our recent 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.

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

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.

Conclusions

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

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.

Conclusions

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.

Wayland MA Source: http://bit.ly/1N1TyRk

Russell’s Garden Center, on Route 20, a family-owned business established in 1876, is a unique Wayland MA institution. When you shop at Russell’s and approach the check-out counter with your plants, flowers, or other purchases, you will see a donation box for a rare-disease charity called “Our Promise to Nicholas Foundation”.

This charity is named for Nicholas R. Dainiak, a Bedford MA boy who died on his 11th birthday in 2014, after “a courageous six year battle with Batten’s disease”. The primary mission of the foundation is to raise funds and create partnerships aimed at promoting awareness, providing education, and developing translational research in Batten disease.

One of the events that the Foundation sponsors in order to raise funds and awareness is the John Tanner Memorial 5-K Run and Walk, which this year took place on October 4, 2015 in Wayland. This event memorializes both Nicholas and John Tanner. John Tanner was a competitive runner who devoted all of his races over 5 years to raising awareness about Nicholas and Batten disease. He was also a long-time employee of Russell’s Garden Center—hence the Russell’s and Wayland connection to the Foundation. John Tanner died unexpectedly while running the NYC half marathon in the spring of 2013.

Batten disease

Batten disease is a very rare, fatal, autosomal recessive neurodegenerative disorder that usually begins in childhood. Juvenile Batten disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs). NCLs may be caused by one of over 400 different mutations. They affect the nervous system with vision loss, seizures, movement disorders, slow learning, altered thought processes, and cognitive decline.

Although Batten disease was originally used to describe only the juvenile form of NCL the term “Batten disease” is now widely used to refer to all forms of NCL, including adult-onset disease. Juvenile NCL, the most prevalent form of Batten disease, has been linked to mutations in the CLN3 gene. Late infantile NCL has been linked to mutations in NCL2.

Batten disease is a type of lysosomal storage disease. The CLN3 gene codes for a protein called battenin, which is found principally in lysosomes and in endosomes. The protein’s function is currently unknown. The CLN2 gene codes for a lysosomal enzyme called tripeptidyl peptidase 1 (TPP1), which is an acid protease.

Mutations in CLN2, CLN3, and other Batten disease genes result in the accumulation of lipofuscins in the tissues of the body. Lipofuscins are lipoproteins that form autofluorescent ceroid (i.e., waxy) deposits throughout the body of Batten disease patients.  Lipopfuscin deposits can sometimes be detected visually in the back of the eye. As the disease progresses, the deposits in the retina appear more pronounced, and ophthalmologists see circular bands of different shades of pink and orange in the patient’s optic nerve and retina. Ceroid lipofuscins are a hallmark of Batten disease, and appear to cause disease symptoms.

Juvenile Batten disease has an estimated incidence between 0.5 – 8 per 100,000 live births, with an average of 1.2. Despite its rarity, juvenile Batten disease appears to be the most common form of pediatric neurodegenerative disease. In addition to Batten disease patients, there are approximately 440,000 asymptomatic people in the United States who are carriers of juvenile Batten disease who have one copy of a mutated version of the CLN3 gene.

As with other rare diseases, a typical Batten disease patient may visit 8 physicians and receives 2 to 3 misdiagnoses before being correctly diagnosed. This may take many years. In the case of Nicholas, he had several misdiagnoses and mis-treatments over the early course of his disease, from age 4 to age 5. It was a ophthalmologist who finally correctly diagnosed Nicholas with Batten disease.

Relationship between Batten disease and more common neurodegenerative diseases

The written material next to the donation box for “Our Promise to Nicholas” in Russell’s Garden Center claims that study of Batten disease may lead to a greater understanding of such neurodegenerative diseases of aging as Alzheimer’s and Parkinson’s disease. Some of the symptoms and consequences of Batten disease resemble those of Alzheimer’s and Parkinson’s. Nevertheless, Batten disease is classified as a lysosomal storage disease, while Alzheimer’s and Parkinson’s are thought to be caused via other mechanisms.

However, some researchers see common mechanisms in the pathobiology of neurodegenerative lysosomal storage diseases such as Batten and of other neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Specifically, these include impairment of autophagy and increase in cytoplasmic protein aggregation. For example, some researchers have found relationships between mutations in the Alzheimer’s disease-related protein presenilin 1 and lysosomal dysfunction.

Since clinical trials of drugs for Alzheimer’s disease have so far been unsuccessful, study of alternative mechanisms for the pathogenesis of Alzheimer’s may be useful in developing new ways of addressing drug discovery for this devastating and all-too-common disease.

Discovery and development of gene therapies for Batten disease

The “Our Promise to Nicholas” website has a page entitled “Where your donations go”. According to that Web page, Nicholas’ disease was caused by a splice mutation in CLN2, which blocked production of TPP1. This is the most common mutation in children with the late infantile subtype of Batten Disease.

The same Web page discusses a gene therapy program led by Beverly Davidson, Ph.D. (then at the University of Iowa, Iowa City, IA), which had been supported by Our Promise To Nicholas Foundation. As of April 2014, Dr. Davidson joined the Children’s Hospital of Philadelphia (CHOP). At that time, Dr. Davidson became the director of CHOP’s Center for Cellular and Molecular Therapeutics. She has also continued her research on gene therapy for neurodegenerative diseases, including Batten disease, other neurologic lysosomal storage disorders, Huntington’s and Alzheimer’s diseases, and others.

While at Iowa, and continuing at CHOP, Dr. Davidson and her colleagues were investigating the use of adeno-associated virus (AAV) vectors carrying a functional TPP1 gene in treatment of late infantile Batten disease in animal models.

On November 11, 2015, Spark Therapeutics (Philadelphia, PA) announced that its first gene therapy program targeting a central nervous system (CNS) disease will target late infantile Batten disease. In that press release, it also announced that a report published in the 11 November issue of Science Translational Medicine provides preclinical proof of principle for Spark’s gene therapy, known as SPK-TPP1. The preclinical study, in a naturally occurring dog model, was led by Dr. Davidson at CHOP.

The study demonstrated the potential of a one-time administration of SPK-TPP1 to delay onset and progression of Batten disease in the dog model. SPK-TPP1 consists of Spark’s AAV2 vector carrying a functional TPP1 gene. The preclinical study showed that one-time administration of SPK-TPP1 to the ependymal cells of the brain ventricular system produced steady expression of the enzyme in the cerebrospinal fluid, and throughout the CNS. It also resulted in delayed onset of clinical symptoms and disease progression, protection from cognitive decline and extension of lifespan, as compared to untreated controls.

Based on these results, Spark plans to initiate Investigational New Drug Application (IND)-enabling studies in 2015.

Our November 2015 book-length report, Gene Therapy: Moving Toward Commercialization (published by Cambridge Healthtech Institute), contains a discussion of gene therapy vectors, including AAV. It also highlights Spark Therapeutics as a leader in AAV-based gene therapy and in gene-therapy treatments for retinal diseases. Spark’s technology platform had been developed over a 20-year period at CHOP.

As also discussed in our November 16, 2015 article on this blog, Spark has recently completed a Phase 3 pivotal trial of SPK-RPE65, a gene therapy for treatment of inherited retinal diseases (IRDs) caused by mutations in the gene for RPE65. SPK-TPP1 uses the same AAV2 vector as SPK-RPE65, and will utilize the same manufacturing processes. AAV2 has a neural tropism. Since the retina is an extension of the brain, researchers can utilize AAV2 vectors to target both tissues.

Conclusions

On the Web page “Where your donations go”, Dr. Davidson says that funding from “family foundations such as Our Promise to Nicholas Foundation” has provided much needed support. Their donations have allowed cutting-edge research to be conducted in a timely manner, rather than months or years after researchers develop the ideas for these studies. Moreover, interacting with Batten disease families is especially motivating, and the advisory role of scientists who review grant proposals for family foundations is valuable as well.

Our Promise to Nicholas is far from the only Batten disease “family foundation”. Other families of patients with juvenile and adult-onset Batten disease have formed foundations to fund research and awareness. For example, there are Nathan’s Battle Foundation and the Batten Disease Support and Research Association (BDSRA). Our Promise to Nicholas participated in the 2015 BDSRA Annual Conference, and worked together with other Batten disease family foundations to provide nursing care and childcare for the event. Thus when Dr. Davidson refers to “family foundations”, she is referring to several such organizations.

Dr. Davidson also pointed out that grant funding from the National Institutes of Health (NIH) has dramatically decreased in recent years due to Federal budget constraints. This has especially affected research on rare diseases such as Batten disease. Dr. Davidson believes that “family foundation support is being increasingly relied upon to fill a growing void in NIH funding”.

Funding of Dr. Davidson’s research by Our Promise to Nicholas Foundation and other family foundations has resulted in a gene therapy R&D program that has been adopted by one of the world’s leading gene therapy companies, Spark Therapeutics. Spark (in collaboration with Dr. Davidson’s group at CHOP) is taking its Batten disease program into the clinic, and intends to commercialize SPK-TPP1. Spark is also using its Batten disease program as the basis for its larger neurodegenerative disease program. Thus Our Promise to Nicholas Foundation has much to be proud of.

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.