Opportunity for Enhancing Immunotherapeutic Drug Efficacy

The emergence of immuno-oncology drugs – therapeutics designed to spur engagement of the host immune system against cancer cells – has transformed the treatment of cancer. Since approval of the first immuno-oncology agent in 2011, 11 drugs have been approved in the U.S. to date and they have become the standard of care in a number of cancer types, including melanoma, lung and kidney cancers1. Hundreds of other compounds are in development.

These compounds encompass a wide range of therapeutic strategies, including checkpoint inhibitors, T-cell targeted immuno-modulators such as CART-T therapies, cancer vaccines, oncolytic viruses, and next generation, bi-specific antibodies. All these approaches rely on the presence of tumor antigens – proteins present on tumor cells that allow the immune system, and immuno-oncology agents to recognize and target these cells.

Despite the dramatic results generated by immuno-oncology therapies to date, they have produced sustained therapeutic benefit in only a subset of patients. For example, the average response rate to checkpoint inhibitors, across a range of tumors, is approximately 30 percent of patients. For CART-T therapy, initial response rates are high but many patients relapse.

Recent research suggests that one reason patients do not respond to immuno-oncology therapies is an insufficient number, or density, of tumor antigen targets. For example, the beneficial responses to checkpoint inhibitors directly correlate with high numbers of tumor mutations and a resulting increase in the number of tumor antigens2. In acute lymphoblastic leukemia patients treated with an experimental CAR-T therapy directed at CD22, there were significant response rates in those patients with high levels of CD22. Tumors in those patients, who had been treated with CAR-T therapy directed at another tumor antigen, CD19, had escaped immune recognition and destruction by downregulating CD193.

1 Tang, et al., Nature Reviews Drug Discovery, 2018. Trends in the Immuno-oncology landscape.
2 Yarchoan, et al., New England Journal of Medicine, 2017; Tumor Mutational Burden and Response Rate to PD-1 Inhibition.
3 Fry et al., Nature Medicine, 2018. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy.

Bryologyx’s lead program

Many tumors are ‘cold’, i.e. unresponsive to immuno-oncology drugs because of insufficient tumor numbers of tumor antigens.

A.

(A) Bryostatin stimulates the expression of tumor antigens on the cancer cell surface to make them ‘hot’.

B.
(B) enabling the immune system to recognize tumors
C.
(C) and destroy them
D.
(D) when immune cells are activated through the use of immuno-oncology drugs.

Many tumors are ‘cold’, i.e. unresponsive to immuno-oncology drugs because of insufficient tumor numbers of tumor antigens (A); Bryostatin stimulates the expression of tumor antigens on the cancer cell surface to make them ‘hot’ (B), enabling the immune system to recognize tumors (C) and destroy them (D), when immune cells are activated through the use of immuno-oncology drugs.

Bryologyx is developing its lead compound, bryostatin-1 to enhance and extend the activity of immuno-oncology drugs by increasing the production of tumor antigens visible to the immune system. That is, to make ‘cold tumors,’ not responsive immuno-oncology agents, ‘hot’. Bryostatin-1 is a complex natural product, that has generated intense scientific interest at the National Institutes of Health and elsewhere, but whose development has been limited until now by supply. The emergence of immuno-oncology provides a new opportunity to capitalize on bryostatin-1’s immune stimulating activity. The company’s program builds this knowledge, earlier clinical oncology experience with the compound in more than 1100 patients, and the development of the first, cost-effective, fully synthetic production method. Bryologyx has exclusive rights to the production method for use in cancer and HIV. Bryostatin-1 has been shown in multiple studies to stimulate increases in a number of tumor antigens associated with B cell cancers, including leukemias, lymphomas and multiple myeloma, and induces immune stimulatory signaling for T-cells without apparent general immune activation. Preclinical proof of concept of bryostatin’s potential to enhance the response to an immuno-oncology therapy has been demonstrated by researchers at the National Cancer Institute. In a murine model of acute lymphoblastic leukemia, the researchers demonstrated that bryostatin-1 significantly increased the response to a CAR-T therapy by increasing expression of the CAR-T target, CD22. Treatment with the CAR-T CD22 alone delayed by did not prevent tumor progression due to low levels of CD22. Results from these studies were presented at the American Society for Hematology (ASH) conference in 2017.

Development Path

The Bryologyx development program is focused initially on B-cell cancers. Based on the human safety data from previous clinical trials with bryostatin-1, and the company’s progress to date, Bryologyx is on a path to initiate clinical studies in late 2020 with bryostatin-1 in combination with an immuno-oncology drug. At the same time, the company is evaluating bryostatin-1’s potential in a range of solid tumors.

Bryostatin-analogs for HIV

One of the key challenges in treating HIV is the virus’ ability to remain latent in infected T-cells, and inaccessible to immune effectors or antiviral drugs, which are effective only when the virus is active. Latent infection remains a threat to patients throughout their lives and the singular barrier to curing the disease. Bryologyx is developing analogs of bryostatin with potential to reverse HIV latency, potentially making the virus vulnerable to attack by drugs or the immune system. Cell-based and animal research with bryostatin-1 has demonstrated the potential of this ‘kick and kill’ strategy, but the therapeutic index for bryostatin-1 is insufficient for progression to the clinic. Preclinical studies have demonstrated proof of principle that bryostatin analogs have an improved therapeutic index (Marsden et al., 2017).