Until now, inhibition of phosphoinositide 3-kinase-d in cancer has been limited to leukemias and lymphomas because the isoform is only expressed on immune cells. A new finding that links the kinase to T cell responses in a range of solid tumor types could expand use of the inhibitors and launch a new class of immunotherapies.1

The team behind the study is planning a clinical trial of an undisclosed phosphoinositide 3-kinase-d (PI3Kd) inhibitor in solid tumors.

PI3Kd is one of four PI3K isoforms that play key roles in cell growth, differentiation and survival. The PI3Kα and PI3Kb isoforms are expressed in nearly all cell types and have been targeted in solid tumors, whereas the PI3Kg and PI3Kd isoforms are found primarily on immune cells.

Several companies are developing inhibitors of PI3Kd for hematological malignancies, autoimmune diseases and inflammatory indications in which the isoform is overactive (see "A peek at PI3K inhibitors").

In a series of studies over the last decade, the team's principal investigators, Bart Vanhaesebroeck and Klaus Okkenhaug, studied a mutant, catalytically inactive form of PI3Kd and showed the subtype to be important for the differentiation, expansion and normal function of T and B cells.2-5

Vanhaesebroeck is a professor of cell signaling at the University College London Cancer Institute, and Okkenhaug is group leader in the laboratory of lymphocyte signaling and development at the Babraham Institute.

Vanhaesebroeck told SciBX that for the new study, he and his colleagues initially thought that because mice with mutant Pi3kd have compromised immune responses, they might be more prone to developing solid cancers than wild-type mice.

However, when the researchers established tumors in mutant Pi3kd mice with cells from breast, lung and other solid tumors, they saw the opposite of what they expected. The mutant mice developed smaller primary tumors and fewer metastases and survived longer than wild-type mice given the same treatment.

In addition, PI-3065-a PI3Kd inhibitor from Roche's Genentech Inc. unit-decreased growth of breast and pancreatic tumors in wild-type mice and increased survival compared with vehicle.

PI-3065 was originally developed by Piramed Ltd., which was acquired by Roche in 2008.

Next, the team investigated the link between PI3Kd inhibition and its effects on the immune system in solid tumors and focused on several T cell populations that have known roles in antitumor immunity.

In mice, mutant Pi3kd moderately reduced the activity of tumor antigen-specific Cd8+ T cells but inactivated Treg cells that ordinarily eliminate Cd8+ T cells. Because Pi3kd deficiency had a larger impact on Treg cells than on the Cd8+ T cells, the net result was a gain in antitumor immunity.

Furthermore, in mice with pancreatic tumors, PI-3065 decreased the number of Treg cells in draining lymph nodes and increased the number of Cd8+ T cells in primary tumors and in draining lymph nodes.

The team concluded that Pi3kd suppression enhanced antitumor immune responses in the mice.

The team included researchers from the Medical Research Council's Harwell campus, Queen Mary University of London and Roche's Genentech and Piramed units who assisted with the PI-3065 experiments.

Results were published in Nature.

Taken together, the team's findings suggest that PI3Kd inhibitors could treat solid tumors by "tipping the immune system balance in favor of the tumor-targeting CD8+ T cells," Vanhaesebroeck told SciBX.

The team is also elucidating the mechanism by which PI3Kd deficiency deactivates Treg cells in the cancer models and has a manuscript under review showing that PI3Kd is expressed in some solid tumors, in which it appears to play a role in tumor cell invasion.

Swaroop Vakkalanka, president of Rhizen Pharmaceuticals S.A., agreed that the findings support the potential of PI3Kd inhibitors to treat solid tumors and said that the Nature report begins to shed light on precisely how PI3Kd inhibition exerts its therapeutic effects in those cancers.

He added that his company has unpublished preclinical data showing the efficacy of a dual PI3Kg and PI3Kd inhibitor in solid tumors. Rhizen will decide whether to develop this compound and its PI3Kd-specific inhibitor for solid tumors after conducting additional preclinical studies, he told SciBX.

Delivering delta inhibitors

According to Vanhaesebroeck, PI3Kd inhibitors could be used as immunotherapies in combination with other cancer therapies-including surgery and radiation-or even as adjuvants to cancer vaccines.

"We know from clinical trial data that PI3Kδ inhibitors are safe and well tolerated by cancer patients, some of whom have received the inhibitors for up to three years," he said. "Stimulating the immune system with something that we already know is safe will open a lot of doors for treating solid tumors."

Lori Friedman, senior director of translational oncology at Genentech and coauthor of the Nature study, agreed. But to identify which patients might benefit from PI3Kd inhibitor therapy, she said that "clinical researchers will need to analyze a variety of solid tumor types to understand which ones rely on Treg cells for evading immune responses."

In addition, they will need to investigate how PI3Kd inhibition affects the balance of Treg and CD8+ T cell responses in patients, she said.

Vakkalanka added that using PI3Kd inhibitors in combination with other cancer therapies could have additive or synergistic effects that lower the effective doses and thereby provide an added margin of safety for each therapy.

However, he also wanted to see preclinical and clinical studies combining a PI3Kd inhibitor with immunotherapies that enhance T cell activity against cancer, such as antibodies against programmed cell death 1 (PDCD1; PD-1; CD279). "A PI3Kd inhibitor could support the effectiveness of those therapies in treating cancer by inactivating Treg cells and exerting a broad anti-inflammatory effect," he said.

Because activating mutations in PI3Ka frequently occur in solid tumors, the Nature findings also point to the possibility that inhibiting both PI3Ka and PI3Kd could have therapeutic advantages over inhibiting only PI3Kd, Friedman said.

Indeed, Genentech is interested in determining whether its small molecule PI3K inhibitor pictilisib (GDC-0941; RG7321) has an immunomodulatory effect via PI3Kd inhibition in patients with solid tumors, in addition to having a direct effect on tumor growth via PI3Ka inhibition, Friedman told SciBX.

Pictilisib is in Phase II testing to treat breast cancer and non-small lung cell cancer (NSCLC). The compound inhibits all four PI3K isoforms with nanomolar potency and is more potent against the PI3Ka and PI3Kd isoforms.6

However, Vakkalanka said that inhibiting both PI3Ka and PI3Kd would not be desirable because the safety profiles of pan-PI3K inhibitors are not as good as those of isoform-specific inhibitors. Thus, he cautioned that finding inhibitors specific for the PI3Kd isoform would be important for retaining a good safety profile.

Vanhaesebroeck agreed. "Immune cells express the a isoform as well as the d isoform, and some literature studies suggest that inhibiting both isoforms severely compromises the function of immune cells," he said. This means that "hitting too many PI3K isoforms might override the immunotherapeutic effects" of inhibiting PI3Kd.

Vanhaesebroeck said that the team is planning a clinical trial of an undisclosed PI3Kd inhibitor to treat an undisclosed solid tumor type. "We want to look for early evidence that PI3Kd inhibition has an immunomodulatory effect on solid tumors," he told SciBX.

The findings are not patented or licensed, he said.

Genentech declined to disclose the development status of PI-3065.

Haas, M.J. SciBX 7(25); doi:10.1038/scibx.2014.726 Published online June 26, 2014

REFERENCES

1.   Ali, K. et al. Nature; published online June 11, 2014; doi:10.1038/nature13444
Contact: Bart Vanhaesebroeck, University College London Cancer Institute, London, U.K.
e-mail: bart.vanh@ucl.ac.uk

2.   Okkenhaug, K. et al. Science 297, 1031-1034 (2002)

3.   Ali, K. et al. Nature 431, 1007-1011 (2004)

4.   Okkenhaug, K. et al. J. Immunol. 177, 5122-5128 (2006)

5.   Bilancio, A. et al. Blood 107, 642-650 (2006)

6.   Fulmer, T. BioCentury 20(9) A9-A13; Feb. 27, 2012

COMPANIES AND INSTITUTIONS MENTIONED

Babraham Institute, Cambridge, U.K.

Genentech Inc., South San Francisco, Calif.

Medical Research Council, Harwell, U.K.

Queen Mary University of London, London, U.K.

Rhizen Pharmaceuticals S.A., La Chaux-de-Fonds, Switzerland

Roche (SIX:ROG; OTCQX:RHHBY), Basel, Switzerland

University College London Cancer Institute, London, U.K.