Targeting solid tumors with natural killer (NK) cells

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.


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