This Dutch biotech startup is quietly developing a novel immune-cell approach for cancer. Can it muscle in on established rivals?

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The News:

Lava Therapeutics BV (Hertogenbosch NLD) is quietly developing a cancer immunotherapy that arms a rare type of immune cell called gamma delta T cells, Labiotech.eu reports. The company’s mission is to develop antibodies that recruit innate immune cells near tumors and activate them to kill cancer cells.

T cells are immune cells that have a strong potential for use in cancer immunotherapies, including CAR-T and checkpoint inhibitors. Unlike the T cells used in most immunotherapies, Lava’s focus is on gamma delta T cells. Making up less than 5% of T cells in the body, they are a vital part of the immune system’s tumor surveillance squad, with their eyes peeled for stressed cells, a sign of cancer.

“Gamma delta T cells are continuously on the lookout for stressed cells and if they find a stressed cell, they kill it,” Erik Ensing, Lava’s Director of Business Development, told Labiotech.

Recruiting gamma delta T cells in cancer immunotherapy has a crucial advantage over using other T cells. Unlike the other 95% of T cells, gamma delta T cells are oriented toward identifying stressed cancer cells rather than healthy cells, making them potentially safer in immunotherapy. To activate gamma delta T cells, Lava uses bispecific antibodies that attach both to tumor cells and T cells, activating the immune cells and causing the tumor cells’ demise. Bispecific antibodies are also being developed by biotechs like Affimed NV (Heidelberg DEU) and Roche Holding AG (Basel CHE), activating regular T cells to treat different types of cancer.

A problem with bispecific antibodies targeting regular T cells is that they can also activate cells that suppress the immune system response, reducing their own effectiveness. By targeting only the gamma delta T cells, Lava hopes to avoid this issue.

“We do not touch the suppressive T cells within the tumor environment, so we believe that we can gain some efficacy,” Ensing elaborated.

Lava raised €16M in May, and is currently selecting promising candidate drugs for liquid and solid tumors.

“We are about to select a clinical candidate, and start preclinical development,” Ensing said. “We expect to be in the clinic with our first compound by the end of 2020.”

Steve’s Take:

Leave it to Labiotech.eu to flush out a diamond in the rough, tough-sledding, crowded field of immune system-based drug development. Theirs is a relatively new twist on the regular T-cell approach.

But first, let’s take a brief look at Lava Therapeutics’ main competitors in the immune-systems race to riches, as assembled by Owler. Several announced breaking news earlier in the week with excerpts from press releases therefrom.

Then with the help of Labiotech.eu, we’ll chart the likely, extremely arduous route for Lava Therapeutics’ trip to the regulatory finish line where an approval could spell a veritable jackpot.

1) Exelixis Inc. (South San Francisco)

Michael M. Morrissey, President & CEO

372 employees

$118.3M total funding

$743.9M revenue

Publicly traded

Dec. 5, 2018. (BUSINESS WIRE) Exelixis Inc. and Ipsen SA (Paris) today announced the initiation of COSMIC-312, a Phase 3 pivotal trial of cabozantinib (CABOMETYX) in combination with atezolizumab (TECENTRIQ) versus sorafenib in previously untreated advanced hepatocellular carcinoma (HCC). The co-primary endpoints of the trial are progression-free survival and overall survival. An exploratory arm will also evaluate cabozantinib monotherapy in this first-line setting.

Exelixis is sponsoring COSMIC-312, and Ipsen will co-fund the trial. Ipsen will have access to the results to support potential future regulatory submissions outside of the US and Japan. Genentech, a member of the Roche Group, is providing atezolizumab for use in this trial.

2) Endocyte Inc. (West Lafayette IN)

Mike A. Sherman, President & CEO

44 employees

$160M funding

<$1M revenue

Private

3) MacroGenics Inc. (Rockville MD)

Scott Koenig, President & CEO

330 employees

$228.6M funding

$196.7M revenue

Publicly traded

Dec. 3, 2018 (GLOBE NEWSWIRE)–MacroGenics Inc., a clinical-stage biopharmaceutical company focused on discovering and developing innovative monoclonal antibody-based therapeutics for the treatment of cancer, today announced clinical data from an ongoing Phase 1 study of flotetuzumab, MacroGenics’ CD123 x CD3 bispecific DART molecule in relapsed/refractory patients with acute myeloid leukemia (AML) The data were presented in two oral and two poster presentations at the 60th Annual Meeting of the American Society of Hematology (ASH), taking place in San Diego, CA on December 1-4, 2018.

“Overall, the results presented at ASH have provided new insights and support the continued study of flotetuzumab in AML patients, including those with refractory AML,” said Scott Koenig, MD, PhD, President and CEO of MacroGenics. “[The company] intends to initiate a combination study of flotetuzumab and MGA012, an anti-PD-1 agent, in 2019, guided by ongoing optimization of the monotherapy dosing regimen,” Koenig added.

4) Array BioPharma Inc. (Boulder CO)

Ron Squarer, CEO

298 employees

$68.8M funding

$200.9M revenue

Publicly traded

5) ImmunoGen Inc. (Waltham MA)

Mark Enyedy, President & CEO

293 employees

$1M funding

$79.5M revenue

Publicly traded

6) Seattle Genetics Inc. (Bothell WA)

Clay B. Siegall, President & CEO

1,100 employees

$60.5M funding

$564.6M revenue

Publicly traded

Dec. 4, 2018. (RTTNews.com) Seattle Genetics Inc. and Japan’s Takeda Pharmaceutical Co. Ltd. announced late Monday positive data from the ECHELON-2 phase 3 clinical trial for ADCETRIS (Brentuximab Vedotin) in frontline treatment of CD30-Expressing Peripheral T-Cell Lymphomas.

The data demonstrated that frontline treatment with ADCETRIS (brentuximab vedotin) in combination with CHP (cyclophosphamide, doxorubicin, prednisone) is effective in extending progression-free survival and overall survival with a safety profile comparable to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), a current standard of care in patients with CD30-expressing peripheral T-cell lymphomas or PTCL.

ADCETRIS is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on the surface of several types of PTCL. The data were presented in an oral session at the 60th American Society of Hematology (ASH) Annual Meeting. These data were also simultaneously published online in The Lancet.

7) Agios Pharmaceuticals Inc. (Cambridge MA)

David Schenkein, CEO

274 employees

$217.5M funding

$46.7M revenue

Publicly traded

8) Morphotek Inc. (Exton PA). Unit of Eisai Inc, a part of Japanese drug firm, Eisai

Dr. Nicholas C. Nicolaides, President & CEO

61 employees

$76M funding

$34.5M revenue

9) Nektar Therapeutics Corp. (San Francisco)

Howard W. Robin, President & CEO

509 employees

$850M funding

$1.2B revenue

Publicly traded

10) Veran Medical Technologies Inc. (St. Louis MO)

Jason Pesterfield, President & CEO

31 employees

$91M funding

<$1M

Privately held

Bottom Line:

I agree with Jonathan Smith at Labiotech that targeting gamma delta T cells could be a safer and more effective immunotherapy for cancer, since they are less likely to target and destroy healthy cells than are regular T cells. Other companies, such as Gamma Delta TherapeuticsGadeta and TC Biopharm, are interested in using gamma delta T cells to overcome the problems of CAR-T in terms of sometimes deadly adverse effects and limitations against solid tumors. However, even with these innovations, cell therapy can be costly and time-consuming. Lava’s approach with bispecific antibodies could circumvent the costs of recruiting these cells against cancer.

Bispecific antibodies are still a rarity in the market. To date, only two such compounds have been approved: Fresenius Biotech and Trion Pharma’s catumaxomab in 2009, and Amgen’s blinatumomab in 2014. They were both approved for the treatment of blood cancer. Since then, there has been an avalanche of interest, with some 30 candidates in clinical trials in 2016, the majority aimed at cancer treatment.

Again, one constant concern with all of these cancer immunotherapies is that they can allow the immune system to attack some normal organs in the body, which can lead to serious side effects such as neurotoxicity causing patient deaths, as in Affimed’s recent Phase 1 trial.

As Lava’s compounds are yet to enter the clinic, it remains to be seen if the company’s gamma delta T-cell targets can alleviate these safety concerns. If they do, get ready for a blizzard of investor dollars. I will keep you posted on the progress.

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