22 October 2018

Nobel Prize in Medicine for discovery of cancer immunotherapy via checkpoint inhibition

By |2018-10-22T14:02:37+00:00October 22, 2018|Biomarkers, Cancer, Cancer immunotherapy, Drug Development, Drug Discovery, Haberman Associates, Immunology, Monoclonal Antibodies, Recent News, Translational Medicine|

Checkpoint inhibitor therapies (NIH)

On October 1, 2018, the The Nobel Assembly at the Karolinska Institute announced that it had awarded the 2018 Nobel Prize in Physiology or Medicine jointly to James P. Allison and Tasuku Honjo for their discovery of cancer immunotherapy via immune checkpoint inhibition.

As is usual, these Nobel Prize awards were made decades after the original discoveries. This is despite the growing importance of immunotherapy in cancer treatment, including the prospect for long-term survival of an increasing number of patients.

As we discussed in our January 9, 2014 article on this blog, the development of checkpoint inhibitors was made possible by a line of academic research on T cells that was begun in the 1980s by James P Allison, Ph.D., one of the 2018 Nobel laureates. Dr. Allison’s research focused on targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on activated T cells in tumors.

Even after Dr. Allison’s research demonstrated in 1996 that an antibody that targeted CTLA-4 had anti-tumor activity in mice, no pharmaceutical company would agree to work on this system. However, the monoclonal antibody (mAb) specialist company Medarex licensed the antibody in 1999. Bristol-Myers Squibb (BMS) acquired Medarex in 2009, and the anti-CTLA-4 mAb ipilimumab (BMS’ Yervoy) was approved in 2011 for treatment of metastatic melanoma. It was the first checkpoint inhibitor to be approved by the FDA.

Meanwhile, Dr. Honjo discovered the T-cell protein PD-1 in 1992. PD-1 (programmed cell death protein 1) acts as a brake on the immune system via a different mechanism. PD-1 became a target for other checkpoint inhibitors, notably nivolumab (BMS’ Opdivo—originally developed by Medarex and Ono Pharmaceutical) and pembrolizumab (Merck’s Keytruda). The FDA approved nivolumab for treatment of metastatic melanoma in 2014, and it approved pembrolizumab for the same indication, also in 2014.

Since 2014, clinical studies—and regulatory approvals—of checkpoint inhibitor therapies have been expanded to other types of cancer (e.g., lung and renal cancers, lymphomas). They now also include mAb agents that target yet another checkpoint protein, PD-L1. (programmed death-ligand 1).  Moreover, clinical studies of combination therapies of inhibitors of both PD-1 and CTLA-4 in patients with metastatic melanoma showed that the combination therapy is more effective than treatment with either agent alone.

Clinical studies on immune checkpoint therapy have since developed rapidly. Researchers have applied this type of therapy to a wide range of types of cancer, and have also developed additional checkpoint inhibitor drugs. A major reason for the intense interest in checkpoint inhibitor therapy is the potential of these drugs to produce long-term survival. However, only a minority of patients show such dramatic responses. Researchers have therefore been attempting to develop biomarkers and diagnostic tests to identify factors that promote long-term survival in patients. They have also been working to develop potentially more-effective therapies by combining checkpoint inhibitors with other agents. Such attempts to build on prior achievements in immuno-oncology to improve outcomes for more patients are often referred to as “immuno-oncology 2.0.” Agents that are intended to improve the results of treatment with agents like checkpoint inhibitors may also be referred to as “second-wave” or “third-wave” immuno-oncology agents.

Our 2017 report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes  (published by Insight Pharma Reports) focuses on immuno-oncology 2.0 strategies. This report, as well as several articles on this blog, provide updated discussions of approved and clinical stage agents in immuno-oncology (including checkpoint inhibitors and “second-wave” agents). These materials also discuss other classes of cancer immunotherapy agents, such as cancer vaccines and cellular immunotherapies.

Other early immuno-oncology researchers who did not receive the Nobel

As pointed out in the October 1 Nature News article about the Nobel Prize, there were other researchers who made seminal early discoveries in immuno-oncology who were not included in the Nobel Prize. (This usually happens.)

Gordon Freeman, an immunologist at the Dana-Farber Cancer Institute (Boston, MA), was named in the Nature News article as one of these researchers. Dr. Freeman, along with immunologists Arlene Sharpe (Harvard Medical School, Boston MA) and Lieping Chen (Yale University, New Haven, CT), studied checkpoint proteins, especially a protein that binds to PD-1 known as PD-L1. PD-L1 is the target for the approved checkpoint inhibitor mAb agents atezolizumab (Roche/ Genentech’s Tecentriq) and avelumab (Merck/Serono-Pfizer’s Bavencio). Although the CTLA-4 inhibitor ipilimumab was the first checkpoint inhibitor to be approved, it has so far been shown to work only in melanoma. However, PD-1 and PD-L1 inhibitors have been approved for the treatment of 13 different types of cancer so far. According to Dr. Freeman, his discoveries and those of his collaborators “were foundational” in the development of PD-1 and PD-L1 inhibitors.

Nevertheless, Dr. Freeman also said that Dr. Allison’s work with CTLA-4 was foundational for the development of the field of immuno-oncology, beginning when most researchers and pharmaceutical companies considered it to be scientifically premature. “Jim Allison has been a real advocate and champion of the idea of immunotherapy,” he said. “And CTLA-4 was a first success.”

All in all, Dr. Freeman says that it has been exciting to watch the immuno-oncology field develop. Not only has this development involved “an incredible amount of human creativity and energy,” but many cancer patients are doing better as the result of the entry of immuno-oncology drugs into the oncologist’s armamentarium.

Also as usual, Drs. Allison and Honjo received other prestigious awards prior to receiving the Nobel. In 2015, Dr. Allison received a Lasker prize for his work in cancer immunotherapy. (Lasker awards are commonly called the “American Nobels”). Dr. Honjo won the Kyoto Prize in basic sciences in 2016. This is a global prize awarded by the Inamori Foundation.

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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.

14 March 2018

MIT study finds that the probability of clinical trial success is nearly 40% higher than previously thought

By |2018-11-07T18:18:58+00:00March 14, 2018|Biomarkers, Cancer, Drug Development, Haberman Associates, Immunology, Personalized Medicine, Recent News, Strategy and Consulting, Translational Medicine|

NIH Clinical Center

On December 7, 2017 we published an article on this blog entitled ”Improving Candidate Selection: Translating Molecules into Medicines”. This article was based on a December 4, 2017 symposium sponsored by Aptuit entitled “Improving Candidate Selection: Translating Molecules into Medicines”. The focus of the meeting was on improving drug candidate selection in order to improve development success.

Our article stated that “Only about 10% of drug candidates make their way from first-in-humans trials to regulatory approval. The greatest amount of attrition occurs in Phase 2. Approximately half of candidates fail at that stage, mainly due to lack of efficacy.” As we also stated in that article, drug attrition numbers have not changed since our 2009 publications, “Approaches to Reducing Phase II Attrition” and “Overcoming Phase II Attrition Problem”.

However, especially since the year 2000, drug developers have been working with increasingly newer classes of drugs. They attribute continuing high attrition rates to difficulties in working with ever-changing classes of drugs designed to treat complex diseases. Attrition thus continues to be a moving target.

Several more recent estimates of clinical trial success are comparable to those cited by participants in the Aptuit symposium, and in our own 2009 publications. For example, as pointed out by Endpoints News, BIO (the Biotechnology Innovation Organization) in a recent publication analyzing clinical development success rate from 2006 to 2015, determined that the overall likelihood of approval from Phase 1 for all drug candidates was 9.6%, and 11.9% for all indications other than cancer. (The likelihood of approval for oncology candidates was 5.1%; this is about the same as the figure for oncology success cited in our 2009 report.) Meanwhile, AstraZeneca cited a 5% success rate for its own candidates in a January 2018 analysis.

Now comes a January 2018 study by Andrew W Lo, Ph.D. and his colleagues at MIT that concludes that 13.8% of all drug development programs eventually lead to approval. This study was discussed in a February 1, 2018 article in Endpoints News by John Carroll. Dr. Lo is the Director of the MIT Laboratory for Financial Engineering.

As with earlier studies, the success rates depend on the particular indication. For example, infectious disease vaccines have the highest rate of success, 33.4%. Oncology drugs—as in most such studies—have the lowest rate of success—3.4%.

Dr. Lo’s study represents a Big Data approach to determining drug development success rates.The MIT group analyzed a large dataset of over 40,000 entries from nearly 186,000 clinical trials of over 21,000 compounds. To analyze this dataset, the researchers developed automated algorithms designed to trace each drug development path and compute probability of success (POS) statistics in a matter of hours. If generating POS estimates had been done by traditional manual methods, it would have taken months or years.

Despite the intense focus of the biopharmaceutical industry, investors, and the general public on cancer, the POS for oncology drugs has been consistently abysmal for years—as shown by our 2009 report, the 2016 BIO report, and the Lo et al. 2018 MIT study. However, according to the MIT study, although the POS for oncology drugs had the lowest overall approval rate of 3.4% in 2013, it rose to 8.3% in 2015. Both Dr. Lo’s group and John Carroll of Endpoint News attribute this sharp rise to the advent of immuno-oncology drugs.

As we discussed in our February 22, 2018 blog article, “JP Morgan 2018 (JPM18) panel optimistic for new breakthrough immuno-oncology therapies despite a crowded field”, leading researchers in academia and industry believe that because of the strong emergence of immuno-oncology therapies, now is probably the best time for progress in oncology in several decades. This is consistent with the findings of Dr. Lo’s group. However, as we stated in our previous blog article (based on the conclusions of the JPM18 panel), “This historic opportunity would be maximally capitalized if people from academia, industry, regulatory agencies, and nonprofit organizations work together, especially in adopting novel collaborative study design, aimed at bringing the promise of cancer immunotherapies to patients, sooner rather than later.”

Another issue discussed by Dr. Lo and his colleagues in their study is role of biomarkers in the success of clinical trials. The researchers compared POS estimates for trials that stratified patients using biomarkers to those that did not use biomarkers. They found that trials that utilized biomarkers tended to be more successful (by nearly a factor of 2) than those that did not. However, biomarker-stratified trials studied by the MIT group were nearly all in oncology. Therefore, it was not possible for the MIT researchers to obtain valid conclusions on the role of biomarkers for therapeutic areas outside of oncology.

Nevertheless, with the continuing development of oncology biomarkers, coupled with breakthrough R&D results in immuno-oncology, the MIT researchers expect that the rates of approval of cancer drugs will continue to improve.

Conclusions

Dr. Lo’s group intends to provide continuing information on the success rates of clinical trials, beyond this initial study. The goal is to provide greater risk transparency to drug developers, investors, policymakers, physicians, and patients, order to assist them in their decisions.

Moreover, our book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes can help you understand the role of advances in immuno-oncology in the current and expected increases in drug development success in the cancer field.

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.

21 December 2017

FDA approves Spark Therapeutics’ retinal disease gene therapy Luxturna, a month ahead of schedule

By |2018-09-12T21:33:46+00:00December 21, 2017|Drug Development, Eye Diseases, Gene Therapy, Haberman Associates, Personalized Medicine, Rare Diseases, Recent News|

Interface of retinal pigment epithelium and photoreceptor cells. Source: NIH Open-i

 

As we discussed in our December 17, 2015 article on this blog, Spark Therapeutics’ (Philadelphia, PA) SPK-RPE65 had achieved positive Phase 3 results at that time. It was expected to reach the U.S. market in 2017.

As announced by Spark in a press release, SPK-RPE65, now known as Luxturna (voretigene neparvovec-rzyl), was approved by the FDA on Dec. 19, 2017. This was ahead of the FDA’s PDUFA date for the therapy (i.e., the deadline for action by the FDA) in mid-January 2018.

Luxturna is a one-time gene therapy designed to treat patients with an inherited retinal disease (IRD) caused by mutations in both copies of the RPE65 (retinal pigment epithelium-specific 65 kDa protein) gene who have sufficient viable retinal cells as determined by their treating physicians. Luxturna consists of a version of the human RPE65 gene delivered via an adeno-associated virus 2 (AAV2) viral vector. It is administered via subretinal injection.

As outlined in the Spark December 19, 2017 press release, Luxturna is first FDA-approved gene therapy for a genetic disease, the first FDA-approved pharmacologic treatment for an inherited retinal disease (IRD), and first adeno-associated virus (AAV) vector gene therapy approved in the United States. However, two gene therapies, uniQure/Chiesi’s Glybera (alipogene tiparvovec) (an expensive money-losing therapy that has only been used once) and GlaxoSmithKline’s Strimvelis, were approved in Europe prior to the FDA approval of Luxturna. Moreover, the CAR-T (chimeric antigen receptor  T-cell) cellular immunotherapies Kymriah (tisagenlecleucel) (Novartis) and Yescarta (axicabtagene ciloleucel) (Gilead/Kite), which are ex vivo gene therapies, were approved in 2017—prior to the approval of Luxturna. Thus although Luxturna is a pioneering gene therapy that represents a number of “firsts”, it is only one of several of the first gene therapies that have reached regulatory approval in recent years.

Pricing and patient access issues with Luxturna

On January 3, 2018, Spark announced that it has set an $850,000 wholesale acquisition cost for Luxturna — $425,000 per eye affected by an RPE65 gene mutation. This makes Luxturna—which is intended as a one-time treatment—the highest priced therapy in the U.S. to date. Some 2,000 patients (fewer than 20 new patients per year) may be eligible for treatment with Luxturna, provided that Spark can persuade payers to cover the treatment.

Also on January 3, 2018, Spark announced a set of three payer programs designed to enable patient access to treatment with Luxturna. These include “an outcomes-based rebate arrangement with a long-term durability measure, an innovative contracting model and a proposal to CMS [The Centers for Medicare & Medicaid Services] under which payments for Luxturna would be made over time.” Spark has reached agreement in principle with Harvard Pilgrim Health Care to make Luxturna available under the outcomes-based rebate program, and under the contracting model that is designed to reduce risk and financial burden for payers and treatment centers. Spark has also reached an agreement in principle with affiliates of Express Scripts to adopt the innovative contracting model.

Spark’s proposal to CMS is based on enabling the company to offer payers the option to spread payment over multiple years, as well as greater rebates tied to clinical outcomes.

As pointed out by John Carroll of Endpoints News, pricing and payer programs that become established for Luxturna may have a wide impact on the whole gene therapy field, in particular gene therapies for hemophilia. As we discussed in our February 2, 2016 blog article, several companies—including Spark—are developing one-time gene therapies for hemophilias A and B. Hemophilia could prove to be the most competitive area of gene therapy in the near future.

Our gene therapy report

Our book-length report, Gene Therapy: Moving Toward Commercialization, contains extensive information on the development of improved gene therapy vectors (especially including AAV vectors). It also contains detailed information on SPK-RPE65/Luxturna and its mechanism of action, as well as on other gene therapies in clinical development (such as those for hemophilia). In addition, it contains information on leading gene therapy companies including Spark. It is an invaluable resource for understanding clinical development of gene therapies, and the academic groups and companies that are carrying out this development.

To order our report, Gene Therapy: Moving Toward Commercialization, please go to 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.

7 December 2017

”Improving Candidate Selection: Translating Molecules into Medicines.”

By |2018-09-12T21:41:42+00:00December 7, 2017|Cancer, Drug Development, Drug Discovery, Gene Therapy, Haberman Associates, Immunology, Monoclonal Antibodies, Oligonucleotide Therapeutics, Recent News, RNAi, Strategy and Consulting|

Bromodomain. A chromatin “reader” that is a target of PPI drug development. Source: WillowW at the English language Wikipedia.

 

Allan B. Haberman, Ph.D. was one of about 25 experts from pharmaceutical, biotechnology, and consulting firms who attended Aptuit’s  one-day think-tank event, ”Improving Candidate Selection: Translating Molecules into Medicines”. This was the third and final such networking and discussion symposium, which was held in downtown Boston, on December 4, 2017. The previous two events in this series had been held in San Francisco (18th & 19th Sept 2017) and in Hertfordshire, UK (22nd & 23rd Oct 2017). The Boston discussion session was preceded by a relaxed networking dinner on the evening of the 3rd.

Attendees and presenters at the Boston meeting were from Shire, Celgene, Forma Therapeutics, Roche, Amgen, Novartis, the Broad Institute, Warp Drive Bio, Mass General Hospital, EnBiotix, Yumanity, and Ra Pharma—among others—as well as from Aptuit and its parent company Evotec.

The focus of the meeting was on improving drug candidate selection in order to improve development success. Only about 10% of drug candidates make their way from first-in-humans trials to regulatory approval. The greatest amount of attrition occurs in Phase 2. Approximately half of candidates fail at that stage, mainly due to lack of efficacy.

One of the key issues discussed in the symposium was the role of the Lipinski Rule of Five—a set of physico-chemical properties that determine the “drug-likeness” of a clinical candidate; i.e., whether a compound is likely to be an orally active drug in humans. Some participants stated that these guidelines had been interpreted too rigidly, and have excluded many potentially good drugs from further development. They stated that the Lipinski rules are only guidelines, and do not replace thinking. (For a similar point of view, see Paul Leeson’s 2012 News and Views article in Nature.) For example, researchers should measure physical properties empirically, rather than inferring them.

The Lipinski rules also exclude whole classes of drug candidates—such as natural products and macrocyclic compounds—from consideration. Before the era of combinatorial chemistry and high-throughput screening, natural products were the mainstay of drug discovery and development.

The Haberman Associates website contains reports, articles, and links to reports that are useful in understanding the issues discussed in the Aptuit symposia. Links to most of these publications can be found on our Publications page. Notably, there is a 2009 report entitled Approaches to Reducing Phase II Attrition, which is available from Insight Pharma Reports. There is also a 2009 article (available on our website at no cost) based on that report, entitled “Overcoming Phase II Attrition Problem.”

Drug attrition numbers have not changed since our 2009 publications. However even back in 2009, pharmaceutical company researchers attributed high attrition rates due to lack of efficacy to companies’ addressing more complex diseases, with the need to discover and develop drugs that have novel mechanisms of action and/or address unprecedented targets. At the December 4 Aptiut symposium, participants similarly attributed high attrition rates to researchers’ tackling new classes of drugs. These included drug classes whose development involves working with premature technologies—e.g., protein-protein interactions (PPIs), gene therapy, RNAi, CAR-T therapies, cancer vaccines, , and combination immuno-oncology therapies.

Working on development of drugs based on premature technologies involves development of enabling technologies that will allow researchers to “move up the technology development curve” and thus to achieve increasing success in drug development. R&D in some of these fields—notably development of checkpoint inhibitors for use in immuno-oncology—has been moving up the technology curve, resulting in notable successes.

Although attrition rates have not changed since 2009, drug developers have been working with increasingly newer classes of drugs. Attrition thus continues to be a moving target.

Among the publications available on our website is our 2012 report—Advances in the Discovery of Protein-Protein Interaction Modulators. As the result of corporate restructuring, this report has not be available anywhere in recent years. However, with the permission of the publisher, Datamonitor Healthcare (a division of Informa), we are now hosting it on our website.

Aptuit’s “Translating molecules into medicines” symposia and improving drug discovery and development

The purpose of Aptuit’s symposia was “to discuss and learn from the experiences of those involved in working at the interface of discovery and development. These meetings were designed to give attendees the chance to build meaningful relationships, challenge their understanding of certain subjects and learn from leading members of their peer group in a non-commercialized setting.”

The organizers of the symposia ask whether “having the flexibility to think beyond established rules and adopting more collaborative development strategies will be just as important as the innovative science and technologies for drug discovery and development.” We at Haberman Associates look forward to assisting you in your efforts to move your drug discovery and development programs forward.

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.

19 October 2017

Can immunotherapy 2.0 strategies save the cancer vaccine field?

By |2018-09-12T21:30:39+00:00October 19, 2017|Cancer, Drug Development, Drug Discovery, Haberman Associates, Immunology, Monoclonal Antibodies, Personalized Medicine, Recent News, Strategy and Consulting, Translational Medicine|

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.

Conclusions

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.