Funding opportunities

Funding Type: 
Disease Team Therapy Development III
Grant Number: 
Principle Investigator: 
Funds requested: 
$19 999 996
Funding Recommendations: 
Grant approved: 
Public Abstract: 

Most normal tissues are maintained by a small number of stem cells that can both self-renew to maintain stem cell numbers, and also give rise to progenitors that make mature cells. We have shown that normal stem cells can accumulate mutations that cause progenitors to self-renew out of control, forming cancer stem cells (CSC). CSC make tumors composed of cancer cells, which are more sensitive to cancer drugs and radiation than the CSC. As a result, some CSC survive therapy, and grow and spread. We sought to find therapies that include all CSC as targets. We found that all cancers and their CSC protect themselves by expressing a ‘don’t eat me’ signal, called CD47, that prevents the innate immune system macrophages from eating and killing them. We have developed a novel therapy (anti-CD47 blocking antibody) that enables macrophages to eliminate both the CSC and the tumors they produce. This anti-CD47 antibody eliminates human cancer stem cells when patient cancers are grown in mice. At the time of funding of this proposal, we will have fulfilled FDA requirements to take this antibody into clinical trials, showing in animal models that the antibody is safe and well-tolerated, and that we can manufacture it to FDA specifications for administration to humans.

Here, we propose the initial clinical investigation of the anti-CD47 antibody with parallel first-in-human Phase 1 clinical trials in patients with either Acute Myelogenous Leukemia (AML) or separately a diversity of solid tumors, who are no longer candidates for conventional therapies or for whom there are no further standard therapies. The primary objectives of our Phase I clinical trials are to assess the safety and tolerability of anti-CD47 antibody. The trials are designed to determine the maximum tolerated dose and optimal dosing regimen of anti-CD47 antibody given to up to 42 patients with AML and up to 70 patients with solid tumors. While patients will be clinically evaluated for halting of disease progression, such clinical responses are rare in Phase I trials due to the advanced illness and small numbers of patients, and because it is not known how to optimally administer the antibody. Subsequent progression to Phase II clinical trials will involve administration of an optimal dosing regimen to larger numbers of patients. These Phase II trials will be critical for evaluating the ability of anti-CD47 antibody to either delay disease progression or cause clinical responses, including complete remission. In addition to its use as a stand-alone therapy, anti-CD47 antibody has shown promise in preclinical cancer models in combination with approved anti-cancer therapeutics to dramatically eradicate disease. Thus, our future clinical plans include testing anti-CD47 antibody in Phase IB studies with currently approved cancer therapeutics that produce partial responses. Ultimately, we hope anti-CD47 antibody therapy will provide durable clinical responses in the absence of significant toxicity.

Statement of Benefit to California: 

Cancer is a leading cause of death in the US accounting for approximately 30% of all mortalities. For the most part, the relative distribution of cancer types in California resembles that of the entire country. Current treatments for cancer include surgery, chemotherapy, radiation therapy, biological therapy, hormone therapy, or a combination of these interventions ("multimodal therapy"). These treatments target rapidly dividing cells, carcinogenic mutations, and/or tumor-specific proteins. A recent NIH report indicated that among adults, the combined 5-year relative survival rate for all cancers is approximately 68%. While this represents an improvement over the last decade or two, cancer causes significant morbidity and mortality to the general population as a whole.

New insights into the biology of cancer have provided a potential explanation for the challenge of treating cancer. An increasing number of scientific studies suggest that cancer is initiated and maintained by a small number of cancer stem cells that are relatively resistant to current treatment approaches. Cancer stem cells have the unique properties of continuous propagation, and the ability to give rise to all cell types found in that particular cancer. Such cells are proposed to persist in tumors as a distinct population, and because of their increased ability to survive existing anti-cancer therapies, they regenerate the tumor and cause relapse and metastasis. Cancer stem cells and their progeny produce a cell surface ‘invisibility cloak’ called CD47, a ‘don’t eat me signal’ for cells of the native immune system to counterbalance ‘eat me’ signals which appear during cancer development. Our anti-CD47 antibody counters the ‘cloak’, enabling the patient’s natural immune system to eliminate the cancer stem cells and cancer cells. Our preclinical data provide compelling support that anti-CD47 antibody might be a treatment strategy for many different cancer types, including breast, bladder, colon, ovarian, glioblastoma, leiomyosarcoma, squamous cell carcinoma, multiple myeloma, lymphoma, and acute myelogenous leukemia.

Development of specific therapies that target all cancer stem cells is necessary to achieve improved outcomes, especially for sufferers of metastatic disease. We hope our clinical trials proposed in this grant will indicate that anti-CD47 antibody is a safe and highly effective anti-ancer therapy that offers patients in California and throughout the world the possibility of increased survival and even complete cure.

Review Summary: 


This application is a continuation of a previous, on-going Disease Team project focused on filing an Investigational New Drug (IND) Application for a therapeutic antibody candidate that targets cancers and their cancer stem cells (CSC). The focus of this proposal is to begin clinical research with the candidate. The applicant proposes to conduct two parallel Phase 1 trials, one in patients with a blood cell cancer and one in patients with solid tumors, to assess the safety and tolerability of the antibody candidate and to investigate mechanism of action, pharmacodynamics, immunogenicity, drug resistance and biomarkers. In addition, once safe dosing levels have been established, product manufacturing activities are proposed to supply future Phase 2 trials. The application proposed additional activities that were deemed out of scope of the RFA, including a Phase 2 trial in a blood cell cancer, a Phase 1b/2 study in a solid tumor setting, and development of a second therapeutic candidate. The review by the Grants Working Group was limited to the proposed in-scope activities with the expectation that the proposed budget would be reduced accordingly. The out of scope activities are ineligible for funding and the GWG score reflects a review of only the in-scope activities.

Significance and Impact
- Strong preclinical data are presented; if the candidate is similarly active in humans, it would be superior to most existing therapies and could have a significant impact.

- If the candidate therapeutic works in even one of the indications the applicant proposes testing, CIRM will have funded development of an important therapeutic.

- The TPP conveys the long-term aspirational attributes and overall intent of the program but lacks mention of the competitive landscape, which needs to be considered.

- There is no discussion as to how this therapeutic candidate compares with competing development programs targeting the same pathway.

- Reviewers pointed out that the candidate antibody therapeutic is not specifically targeted to cancer stem cells (CSC), but kills bulk tumor cells as well. However, although not specific for CSC, reviewers agreed that the evidence provided suggests that CSC are indeed targeted.

Scientific Rationale and Risk/Benefit
- The major strength of this application is the strong underlying science that supports the rationale of the approach.

- The applicant has generated considerable in vitro and in vivo preclinical proof of concept data demonstrating that the candidate is effective at killing CSC and bulk tumor cells and the target appears to be extremely promising. The applicants have performed laboratory studies on clinical samples from the trial to assess the impact of treatment on cancer stem cells, and intend to continue work in this area.

- Based on the preclinical data, there is a reasonable expectation of clinical benefit with a very manageable risk profile. Reviewers were in agreement in their support of the proposed Phase 1 trials.

- One reviewer expressed concern that the mechanism of action is not sufficiently understood, leading to a question about the safety of targeting the proposed pathway.

Therapeutic Development Readiness
- Preclinical data and preliminary toxicology studies have been completed, suggesting a high probability that the team will be able to file an IND and complete the proposed Phase 1 clinical trials within the award period.

- Pre-IND discussions with regulatory agencies have revealed no major concerns.

- The manufacturing plan presented indicates that sufficient clinical grade quantities of the candidate antibody should be available for the start of the clinical program and the manufacturing should not be rate-limiting.

Design and Feasibility
- The proposed clinical studies are well designed; however, reviewers strongly advised staggering the two Phase 1 trials. Reviewers recommended beginning with the solid tumor trial and starting the blood cancer trial after a potentially therapeutic dose level has been achieved in the solid tumor trial.

- Reviewers expressed concern regarding the extraordinary operational complexity of the proposed clinical trials. Conducting international Phase 1 trials requires an unusual degree of coordination and it was not apparent how this would be achieved. Reviewers raised questions regarding how data collection, trial monitoring and integration of the safety results would be conducted and strongly recommended that a more detailed clinical operations plan be reviewed to enhance execution reliability. In addition, it was recommended that product safety should be handled by an experienced and independent drug safety CRO that uses a validated database for pharmacovigilance.

- The application lacked detailed discussion about feasibility and risks for many aspects of the clinical trials including patient recruitment, scheduling of patient visits, and ensuring proper sample collection, data collection and adverse event reporting.

- The manufacturing strategy is established and capable contractors will be making the antibody.

- The enrollment projections and timelines are ambitious and optimistic.

- The Go/No Go decisions are clear and appropriate.

- The development plan to end-of-Phase 2 is very ambitious.

- Reviewers suggested that the applicant will need a broader consultation that includes CIRM to make decisions on where to focus the solid tumor trials following Phase 1. It was also recommended that the development plan would benefit from the integrated development of a predictive biomarker(s).

The FDA has agreed in principle with the applicants’ approach to safety risk management in the clinic, but are waiting to review the full preclinical data package before agreeing to the details of the protocols in the proposed clinical trials.

Principal Investigator (PI), Development Team and Leadership Plan
- This is an excellent team and they have brought on board excellent regulatory, preclinical, clinical and CMC consultants, as well as very capable contractors.

- The project leadership committee and clinical committee are already in place.

- The lead investigators and clinical sites have the relevant experience.

- The overall budget for the proposed project is overly generous.

- Budget costs do not seem to coordinate with the number of patients.

- Site initiation/training costs or related one-time costs for trials are not detailed.

- There are numerous personnel with minimal effort (1%) and it is not clear exactly what role those individuals will have on this proposal. CIRM should monitor the proposal for potential overlap with a pending NIH grant.

- The budget was adjusted to support those activities that fall within scope of the RFA with a direct project cost not to exceed $8,100,000 and total award cost not to exceed $12,726,396.

Collaborations, Assets, Resources and Environment
- While resources necessary for the clinical trials and the supporting studies are in place, reviewers suggested that the investigators would benefit from external clinical monitoring, clinical quality assurance audits, or both. In addition, they recommended that product safety should be handled by an experienced and independent drug safety CRO that uses a validated database.

- The collaboration between the academic partners is well established.

- Although the investigators have leveraged resources with external funding for the initial studies, they have not engaged with an industrial partner. Without an industrial partner, potential further development of the candidate may be limited. This is an extremely competitive field, there are interested companies, and the Applicant should be actively seeking partnerships for the Phase 1b or Phase 2 trials. - It will be essential to have a funding partner on board for late development. Input from that potential funding partner in the design of the Phase 2 trial(s) will help ensure that the type of data that emerges will promote additional participation by the partner in later development.

  • Raj Chopra