17 December 2018

Targeting solid tumors with natural killer (NK) cells

By |2019-04-16T21:53:35+00:00December 17, 2018|Cancer, Cancer immunotherapy, Drug Development, Drug Discovery, Immunology|

Arming NK cells with enhanced antitumor activity. Source: Oberoi P, Wels WS – Oncoimmunology (2013)

I attended and participated in an interactive breakout discussion session entitled “Targeting Solid Tumors with NK Cells” at the Cambridge Healthtech Institute conference “Discovery on Target” on Wednesday, September 26, 2018.

The session moderator was Dan Kaufman, MD, Ph.D., Professor and Director of the Cell Therapy Program, University of California, San Diego. Also among the attendees at the session were several conference speakers.

There is an article in the 14 September issue Science by science writer Mitch Leslie that is relevant to this topic. It focuses on the development of engineered natural killer (NK) cells and macrophages for use in treating various malignancies, especially solid tumors. Several of us referred to that article in our discussion.

A major reason for the interest in developing engineered NK cell therapies for solid tumors is that at least so far treatment with CAR-T cell therapies (chimeric antigen receptor T-cell therapies) has not worked in solid tumors. Solid tumors inhibit entry of CAR-T cells, and suppress those CAR-T cells that are able to enter the tumor. They can also downregulate expression of antigens targeted by the CAR-T cells. We discussed these issues with CAR-T treatment of solid tumors in our 2017 report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes.

Earlier this year Dan Kaufman and his colleagues published a xenograft model study of CAR-NK treatment of human ovarian tumors. They used human NK cells derived from iPSCs (induced pluripotent stem cells), and modified them with a CAR construct containing an NK-derived transmembrane domain. These CAR-NK cells significantly inhibited tumor growth and prolonged survival compared with unmodified NK cells. They also demonstrated in vivo activity similar to that of CAR-T-expressing T cells, but with less toxicity (e.g., excess cytokine release).

So far, nearly all human clinical trials of engineered NK cells (other than in China) are in various types of leukemias and lymphomas, such as a study led by Katy Rezvani of the University of Texas MD Anderson Cancer Center in Houston. In this trial, patients with B cell lymphoma will receive stem cell transplants and chemotherapy before CAR NK cells. Thus, the NK-CAR cells will have fewer cancer cells to deal with than without this pretreatment, and researchers hope that the NK-CAR cells will be able to eliminate the remaining cancer cells.

With respect to engineered NK cell trials in solid tumors, researchers in Germany are testing NK cells with a CAR construct that targets ErbB2 against human glioblastoma. This is the first clinical trial of engineered NK cells against a solid tumor outside of China.

Which solid tumors might be the best targets for engineered NK cells?

Most of the discussion in the breakout session focused on which solid tumors might be the best targets for engineered NK cells. The first “candidate” was acute myeloid leukemia (AML), which is not a solid tumor at all. It is, however, an NK target.

The next candidate was melanoma. Melanoma exhibits low levels of Class I MHC, and thus constitutes an NK target via the “missing self” model of NK recognition. Renal cell cancer (RCC) was also suggested as a candidate. (For example, see this study, which involves enabling NK cells to more efficiently home to RCC.)

Glioblastoma is being targeted by engineered NK researchers (e.g., the German group) because “there is nothing else” in the way of treatment.

Another candidate is viral-induced cancers (See this review for examples of such cancers, including, for example, hepatocellular carcinoma, Burkitt’s lymphoma, and cervical cancer.) NK cells become activated during viral infections and may have the capacity to restrain virus-induced cancers.

Some session participants specifically cited hepatocellular carcinoma (a viral-induced cancer) as a candidate, using local delivery.

Another candidate was the sarcomas, especially synovial sarcoma. Sarcomas may possess NKD2 ligands, which are targets for NKD2 receptors on NK cells.

Session participants stressed that debulking of solid tumors (surgical removal of as much of a tumor as possible) should be done before engineered NK treatment. (This is analogous to the preliminary reduction of most of the cancer cells via conventional methods prior to NK-CAR treatment in the Rezvani B cell lymphoma clinical trial.) Participants also believed that it was important to select a good antigen target for NK-CAR studies.

Combination treatments involving engineered NKs and alternative NK-based therapies

Potential combination treatments involving engineered NKs were also discussed in the session. These included, for example, combining NK-CARs with checkpoint inhibitor antibodies that target PD-1 (e.g., pembrolizumab or nivolumab) or CTLA4 (e.g., ipilimumab).

An alternative NK-based therapy might involve the use of “NK cell engagers”. These are bispecific antibodies that engage NK cells to kill tumor cells.  For example, Innate Pharma has been developing bispecific NK cell engagers that bind with one arm to NKp46 (an activating receptor expressed on all NK cells) and with the other arm to an antigen at the surface of tumor cells.

Gundo Diedrich, Ph.D. of MacroGenics was a speaker at the conference. He gave a presentation on “Development of DART and TRIDENT Molecules to Target Costimulatory and Checkpoint Receptors for Immuno-Oncology Applications”.  DART and TRIDENT refer to MacroGenics’ bispecific and tri-specific antibody platforms for use in immuno-oncology. He also led a breakout discussion on “Considerations in Selecting Bispecific Antibody Formats for Immunotherapies”.

Sources of human NK cells for immunotherapy

We also briefly discussed the issue of sources of human NK cells for immunotherapy, such as cord blood. The Science article by Mitch Leslie discusses this in greater detail. Among the other potential sources are NK cells derived from human iPSCs, such as used in Dr. Kaufman’s study discussed earlier.

The Merck-Dragonfly Therapeutics alliance, October 1, 2018

A few days after the close of the “Discovery on Target” conference, Merck (a cancer immunotherapy leader via its PD-1 inhibitor pembrolizumab) entered into an alliance with Dragonfly, worth a potential $695 million per program. Dragonfly specializes in NK cell engagers The willingness of Merck to enter an alliance with Dragonfly suggests that NK cell-based treatments may become important in cancer immunotherapies.


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.

22 October 2018

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

By |2019-04-16T21:53:35+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.


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.

23 August 2018

NewLink Genetics—new organizational and clinical trial strategy for development of its cancer immunotherapy drug indoximod

By |2018-12-28T23:31:35+00:00August 23, 2018|Cancer, Cancer immunotherapy, Drug Development, Immunology, Translational Medicine|

Indoximod (1-methyl-D-tryptophan)

In Chapter 2 of our 2017 book-length report, Cancer Immunotherapy: Building on Initial Successes to Improve Clinical Outcomes (published by Insight Pharma Reports), we discussed the major approved and emerging checkpoint inhibitors and checkpoint inhibitor modulators. Most of these, exemplified by the PD-1 inhibitors pembrolizumab (Merck’s Keytruda) and nivolumab (BMS’ Opdivo), and the PD-L1 inhibitor atezolizumab (Roche/ Genentech’s Tecentriq), are monoclonal antibodies (mAbs). Chapter 2 also included discussions of several small-molecule checkpoint inhibitor modulators, notably NewLink Genetics’ indoximod (D-1-methyl-tryptophan). Indoximod is an inhibitor of tryptophan catabolism via the kynurenine pathway (also known as the IDO pathway). IDO1 (indoleamine 2,3-dioxygenase 1) is the enzyme that catalyzes the first and rate-limiting step of that pathway.

We also discussed NewLink’s IDO pathway programs in the November 25, 2014 article on this blog.

Recently, on July 31, 2018, NewLink announced that it has decided to focus its indoximod clinical programs on treatment of three specific indications:

  1. recurrent pediatric brain tumors,
  2. front-line treatment of diffuse intrinsic pontine glioma (DIPG),
  3. front-line treatment of acute myeloid leukemia (AML).

These are relatively rare cancer indication with high unmet medical need. NewLink will also continue to advance NLG802, a prodrug of indoximod. NLG802 has demonstrated significantly higher pharmacokinetic exposure in preclinical models.

This program is in contrast to NewLink’s previous clinical trial focus on advanced metastatic melanoma, a more “mainstream” target for cancer immunotherapy. Specifically, the company had been conducting Phase 1/2 studies of combinations of indoximod with the leading checkpoint inhibitors pembrolizumab (Merck’s Keytruda) or nivolumab (Bristol-Myers Squibb’s Opdivo). On April 16, 2018, NewLink announced that it would not proceed to the randomization portion of these Phase 1/2 studies.

NewLink’s change in its clinical trial strategy, as well as its organizational and financial restructuring, was in reaction to the recent Phase 3 failure of Incyte’s IDO-inhibitor drug epacadostat (in combination with pembrolizumab), in late-stage melanoma.

At the time of NewLink’s initial announcement of its change in clinical trial strategy (April 18, 2018), the company’s shares were down 8% premarket. This was despite the simultaneous release of positive preliminary Phase 1 data on the effect of indoximod treatment of children with progressive brain tumors.

Organizational changes in support of NewLink’s new strategy

NewLink has completed a set of organizational changes designed to support its new strategy within its current financial capacity, to substantially cut future expenses, and to extend its cash runway into the second half of 2021. The company is reducing its headcount by approximately 30%, and has made several changes to its senior management, in support of its strategic realignment.

As a result of its organizational changes, NewLink anticipates its current cash runway to extend into the second half of 2021. This excludes any additional financings, proceeds from strategic alliances, and other receipts or expenditures. NewLink expects to expend approximately $10 million per quarter after completing its restructuring.

Mechanistic difference between epacadostat and indoximod

As we discussed in our November 25, 2104 blog post, IDO [and the related enzyme tryptophan-2,3-dioxygenase (TDO)] are enzymes that catalyze the first and rate-limiting step of tryptophan catabolism through the IDO pathway. The resulting depletion of tryptophan, an essential amino acid, inhibits T-cell proliferation. Moreover, the tryptophan metabolite kynurenine can induce development of immunosuppressive regulatory T cells (Tregs), as well as causing apoptosis of effector T cells, especially Th1 cells.

The IDO pathway is active in many types of cancer both within tumor cells and within antigen presenting cells (APCs) in tumor draining lymph nodes. This pathway can suppress T-cell activation within tumors, and also promote peripheral tolerance to tumor associated antigens. Via both of these mechanisms, the IDO pathway may enable the survival, growth, invasion and metastasis of malignant cells by preventing their recognition and destruction by the immune system. Inhibitors of the IDO pathway may therefore block these immunosuppressive pathways, and may therefore enhance the efficacy of checkpoint inhibitor drugs. Development of IDO pathway inhibitors thus constitute an immunotherapy 2.0 strategy.

Epacadostat, Incyte’s drug candidate that failed in the Phase 3 clinical trial, is a direct inhibitor of IDO1.

In contrast, D-1-methyl-tryptophan (NewLink’s indoximod) does not inhibit IDO at all, but inhibits the IDO-related enzyme IDO2.  Indoximod also works to reverse the IDO-mediated inhibition of the immunoregulatory kinase mTOR (mammalian target of rapamycin), and specifically of mammalian target of rapamycin complex 1 (mTORC1), a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.  mTORC1 appears to interpret indoximod as a highly potent mimetic of the amino acid L-tryptophan. It thus can reverse the effects of tryptophan catabolism mediated by the IDO pathway. It is possible that indoximod may be active against tumors driven by any tryptophan catabolic pathway. Indoximod’s unique and complex mechanism of action is not fully understood. Further investigations could thus result in new therapeutic insights. However, current results of mechanistic studies indicate the possibility that indoximod may be a superior agent to epacadostat in potentiating immunotherapeutic efficacy of checkpoint inhibitors.

Moreover, early Phase 2 clinical data on treatment of advanced melanoma patients with a combination of indoximod and the PD-1 inhibitor pembrolizumab indicated that after a median follow-up of 10.5 months, 60 evaluable patients experienced an overall response rate (ORR) of 52%, including six complete and 25 partial responses. The combination therapy was well tolerated.

However, as we discussed earlier, NewLink has shifted its clinical trial program away from melanoma to three rarer cancer indications with high unmet medical need. The outcome of the company’s efforts to develop indoximod awaits the results of the clinical trials in these cancer indications, which are now in the Phase 1b stage.


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.