Guest Column | March 30, 2020

Looking Beyond Alpha-Beta Cells for Cell Therapies, Part 2

By Kyle O’Neil and Peter Bak, Ph.D., Back Bay Life Science Advisors

Kyle O’Neil and Peter Bak, PhD, Back Bay Life Science Advisors
Kyle O’Neil and Peter Bak, PhD, Back Bay Life Science Advisors

As the limitations of chimeric antigen receptor (CAR)-modified αβ T cells have become clearer, cell therapies of the innate immune system (such as γδ T and NK cells) have been advanced to meet unmet needs. In part one, we explored the evolution of these newer approaches to understand the commercial underpinnings and will now take a deeper dive into the potential commercial impact these therapies may offer.

Established NK cell therapy companies are nearing pivotal trials, with next generation approaches just beginning to initiate clinical development (Figure 1). Mature, public NK cell therapy companies Fate Therapeutics and NantKwest are advancing multiple assets in hematologic malignancies and solid tumors. Fate Therapeutics has built a platform of induced pluripotent stem cell (iPSC) derived NK cells (iNKs). The company has aimed to differentiate itself by advancing cell therapies that can be multi-dosed as either monotherapies or combinations, with a low manufacturing cost of $2,500-$3,000/dose.

NantKwest differentiates itself with its platform of NK cells that bind to antibodies, CAR-NK cells, and a combination of the two (5). NantKwest’s lead asset is in a Phase 2 combination study in advanced refractory metastatic Merkel cell carcinoma. Gadeta and TC Biopharm are the leaders in γδ T cell therapy development, having both reached the clinical trial phase and completed deals to advance their platforms. TC Biopharm was founded in 2013 in the UK and has brought its lead asset, an unmodified allogeneic γδ T cell product, into initial human studies in AML. Similarly, Gadeta was founded in 2016 and has built a platform of TEGs, αβ T cells engineered with γδ TCRs. Gadeta’s first TEG was brought into the clinic in 2017 and is also being studied in AML patients. Several earlier-stage companies are beginning to initiate clinical trials, having already built proprietary cell processing platforms. Nkarta Therapeutics’ platform is based on NK cell expansion and cryopreservation technology.

Nkarta is expecting to file three INDs in 2020 for its lead CAR-NK therapies: NKX101, an NKG2D activating receptor engineered to target NKG2D ligands in solid and liquid tumors, and NKX019, which targets CD19. In addition, both GammaDelta Therapeutics and Adicet Bio have built platforms of unique methods to isolate, engineer, activate, and expand γδ T cells.

Differentiated early-stage platform approaches are advancing combination strategies and alternative innate immune cell therapies. Incysus Therapeutics has developed a platform to deliver γδ T cells in combination with chemotherapeutics. Incysus’ lead candidate received IND clearance in April of 2019 in glioblastoma and clinical trials are expected to begin this year.

In contrast, Carisma Therapeutics has built a platform of CAR-engineered macrophages, the antigen-presenting cells of the innate immune system and has announced a lead program targeting HER-2. Takeda has been the most active consolidator in the area, completing deals for both CAR-NK and γδ T cell therapies. In 2017, Takeda signed an exclusive buy-out agreement and equity investment to support moving GammaDelta Therapeutics’ platform into the clinic. The following year, GammaDelta Therapeutics acquired Lymphact, a Portuguese company advancing a subset of γδ T cells called Delta One T (DOT) cells. More recently, Takeda agreed to a licensing pact with MD Anderson Cancer Center for 4 CAR-NK cell therapy programs in 2019, for which it aims to initiate pivotal clinical development in 2021 (6). The programs acquired were “off-the-shelf” therapies that have already been tested on humans. Like NantKwest’s lead asset, the lead CAR-NK in the partnership is “armored” with IL-15, which enhances the proliferation and survival of CAR-NK cells in the body (7). The Takeda program published clinical data from 11 patients in February, highlighting that there were no adverse events, and eight patients had a response (4).

Evolution of Company Financings and Partnering

Investors have an established interest in CAR-NK cell therapies due to the longstanding scientific rationale for NK cells in oncology. Leading companies Fate Therapeutics and NantKwest completed banner IPOs for the space in 2013 and 2015, respectively. Fate Therapeutics’ IPO in October 2013 was priced below expectations, ultimately raising $40M at a valuation of ~$115M. Since then Fate Therapeutics has outperformed, raising its valuation to ~$2B. In contrast, NantKwest raised the largest ever biotechnology IPO at the time in July 2015, reaching a market capitalization of $2.6B. However, the company has underperformed since, losing almost $2B in valuation.

More than $330M has been invested in private innate immune system cell therapy companies since 2016, coinciding with the impressive data generated from first-generation CAR T-cells, their approval, and evidence of limitations in solid tumors (Table 1). Nkarta Therapeutics, the leading private company in next-generation NK cell therapies, was founded based on the interest in NK cells in 2015 during NantKwest’s IPO, subsequently raising $125M over two financings since.

In contrast, γδ T cells were a relatively unknown area for investors until 2015, when a paper demonstrated that γδ T cells are the leukocyte type most correlated with favorable prognostic associations in 25 cancers and 14 solid non-brain tumors (3). This paper sparked a variety of investments in both γδ T-cell targeting antibodies and cell therapies, with γδ T-cell therapy companies having raised more than $152M since 2016. In addition, γδ T-cell companies using an antibody-based approach include Adaptate Biotechnologies, ImCheck Therapeutics, and Lava Therapeutics, which have all completed fundraises since 2017.

Multiple large and mid-cap companies have licensed NK and γδ T-cell therapies, validating earlier-stage VC investments and betting on a variety of approaches. Takeda Pharmaceuticals has completed deals for both CAR-NK and γδ T-cell therapies, with smaller companies such as Regeneron, Celgene (now Bristol- Myers Squibb), Kite Pharma (part of Gilead Sciences), and Bluebird Bio all having completed deals in the space since 2016 (Table 2).

Commercial Implications and the Road Ahead

With an increase in CAR T-cells clinical trials and the growing experience of clinicians using CAR T-cells therapies in a “real world” setting, several potential commercial opportunities have emerged for novel cell-based products:

Due to the time it takes to generate an autologous CAR T-cells option from a patient’s own cells, CAR T-cell therapies are not an option for patients with aggressive/fast-growing cancers. As a result, CAR-NK or γδ T-cell therapeutics may be best used in patients with fast-progressing disease or who have limited immune system function.

Additionally, CAR-NK and γδ T cell therapeutics will likely be explored as combination approaches with a variety of different agents. Since it is unknown why first-line immunotherapeutic options such as PD-1/L1s lead to durable responses in some patients but not others, boosting response rates by even a small amount may be a meaningful clinical improvement to the standard of care, even though combinations in oncology often present cost challenges. This could be particularly beneficial in patients without primary T cells, which are not always present in heavily pre-treated patients.

Further, given the safety/toxicity concerns with CAR T-cells therapies such as cytokine release syndrome and neurotoxicity, use is restricted to the inpatient setting, limiting the eligible patients and presenting reimbursement challenges (8). However, CAR-NK and γδ T cell therapies are aiming to be administered in an outpatient setting due to their clean safety profile and may enable the treatment of more patients (7). Although the implications of outpatient administration for price and reimbursement are nuanced, this may be a significant advantage if considered early in development (9).

Looking Ahead

Beyond the initial clinical positioning of innate immune system cell therapies, there are long-term implications for the promise of safe and “off-the-shelf” therapies. In the future, it is likely that sponsors will take a page from the oncology drug development playbook and begin to explore these products earlier and earlier in the treatment paradigm, assuming cost and reimbursement do not present significant issues. With the growing evidence supporting the biological rationale for NK and γδ T-cell therapies drawing early interest from the VC and biopharma community, clinical evidence of their efficacy or lack thereof will begin to develop. Beyond NK and γδ T cells, there is even interest in developing CAR-based products from cells of other parts of the immune system, such as macrophages.

Despite this, the field is still in early stages, with large pharma partners dipping their toes in the space with licensing agreements rather than outright acquisitions. However, if the key value proposition of these products is validated in early clinical studies, one could envision a “land grab” similar to what was seen at the end of 2017 in the CAR T field, when both Juno Therapeutics and Kite Pharma were acquired by Celgene and Gilead within a five-month period.

About the Authors

Kyle M. O’Neil is an Analyst at Back Bay Life Science Advisors, where he provides strategic guidance to biotech, pharmaceutical, and medical device developers across an array of therapeutic areas.

Peter Bak, Ph.D., a Senior Vice President at Back Bay Life Science Advisors, has more than ten years of experience with a broad range of research approaches—cellular, molecular and biochemical—and fields—from immunology and infection, with emphasis on oncology. Contact the authors at