Cancer is a leading cause of death in California. Research has found that many cancers can spread throughout the body and resist current anti-cancer therapies because of cancer stem cells, or CSC. CSC can be considered the seeds of cancer; they can resist being killed by anti-cancer drugs and can lay dormant, sometimes for long periods, before growing into active cancers at the original tumor site, or at distant sites throughout the body. Required are therapies that can kill CSC while not harming normal stem cells, which are needed for making blood and other cells that must be replenished. We have discovered a protein on the surface of CSC that is not present on normal cells of healthy adults. This protein, called ROR1, ordinarily is found only on cells during early development in the embryo. CSC have co-opted the use of ROR1 to promote their survival, proliferation, and spread throughout the body. We have developed a monoclonal antibody that is specific for ROR1 and that can inhibit these functions, which are vital for CSC. Because this antibody does not bind to normal cells, it can serve as the “magic bullet” to deliver a specific hit to CSC. We will conduct clinical trials with the antibody, first in patients with chronic lymphocytic leukemia to define the safety and best dose to use. Then we plan to conduct clinical trials involving patients with other types of cancer. To prepare for such clinical trials, we will use our state-of-the-art model systems to investigate the best way to eradicate CSC of other intractable leukemias and solid tumors. Finally, we will investigate the potential for using this antibody to deliver toxins selectively to CSC. This selective delivery could be very active in killing CSC without harming normal cells in the body because they lack expression of ROR1. With this antibody we can develop curative stem-cell-directed therapy for patients with any one of many different types of currently intractable cancers.
The proposal aims to develop a novel anti-cancer-stem-cell (CSC) targeted therapy for patients with intractable malignancies. This therapy involves use of a fully humanized monoclonal antibody specific for a newly identified, CSC antigen called ROR1. This antibody was developed under the auspices of a CIRM disease team I award and is being readied for phase I clinical testing involving patients with chronic lymphocytic leukemia (CLL). Our research has revealed that the antibody specifically reacts with CSC of other leukemias and many solid-tumor cancers, but does not bind to normal adult tissues. Moreover, it has functional activity in blocking the growth and survival of CSC, making it ideal for directing therapy intended to eradicate CSC of many different cancer types, without affecting normal adult stem cells or other normal tissues. As such, treatment could avoid the devastating physical and financial adverse effects associated with many standard anti-cancer therapies. Also, because this therapy attacks the CSC, it might prove to be a curative treatment for California patients with any one of a variety different types of currently intractable cancers.
Beyond the significant benefit to the patients and families that are dealing with cancer, this project will also strengthen the position of the California Institute of Regenerative Medicine as a leader in cancer stem cell biology, and will deliver intellectual property to the state of California that may then be licensed to pharmaceutical companies.
In summary, the benefits to the citizens of California from the CIRM disease team 3 grant are:
(1) Direct benefit to the thousands of patients with cancer
(2) Financial savings through definitive treatment that obviates costly maintenance or salvage therapies for patients with intractable cancers
(3) Potential for an anti-cancer therapy with a high therapeutic index
(4) Intellectual property of a broadly active uniquely targeted anti-CSC therapeutic agent.
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 can kill cancer cells and cancer stem cells that express the embryonic cell surface protein ROR1. While ROR1 is typically absent on healthy adult cells, activation of the ROR1 protein promotes survival, proliferation and migration of cancer cells throughout the body. The cellular pathway that ROR1 activates is stimulated in over 90% of people with chronic lymphocytic lymphoma (CLL); in addition, ROR1 expression may be a pathway to resistance particularly for recently developed drugs affecting the BCR, whose dysregulation has been shown to be a hallmark of CLL. The applicant has proposed a Phase 1a/b clinical trial in patients with CLL to identify a safe and efficacious dose of the therapeutic antibody, which could be administered alone, or in combination with, other established chemotherapeutic drugs.
However, the grant application also included activities that were out of scope for RFA 13-01, including the development of a second therapeutic drug candidate and conducting advanced stage clinical trials in new therapeutic indications, for which the applicant presented very preliminary preclinical data. The CIRM Science Office and Grants Working Group considered the following proposed work within scope of the RFA: a single agent Phase 1a trial in CLL, the preclinical studies necessary to support subsequent expansion to the proposed Phase 1b trial in CLL, and the Phase 1b trial in CLL using the therapeutic antibody in combination with other chemotherapies. Accordingly, the requested budget was reduced to reflect support of the in-scope activities and the review of the proposal was limited to consideration of the in-scope activities and their supporting budget. 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
- A therapy for CLL that has minimum off-target cytotoxicity could have a major clinical impact and, as ROR1 is largely absent on healthy adult cells, an antibody that binds to the protein would be expected to have little direct cytotoxic effect on healthy cells.
- The TPP was realistic for the development of a therapeutic for CLL. However, it was not clear whether the team intends to use ROR1 expression to select patients and, if so, whether they currently have assays in place.
- Reviewers noted that there is a number of possible therapeutics for CLL currently in development that may compete with the clinical use of the proposed therapeutic antibody.
Scientific Rationale and Risk/Benefit
- The rationale for the use of the proposed therapeutic antibody in CLL has been well-established in preclinical studies. As the antibody does not appear to bind to normal cells and tissues, the safety profile is likely to be favorable and it is expected that the antibody will have an acceptable therapeutic index.
- There is a reasonable expectation of clinical benefit for CLL patients in the proposed study.
Therapeutic Development Readiness
- Preclinical readiness criteria have been met for the use of the therapeutic antibody as a monotherapy in a Phase 1 clinical trial in CLL. Additional milestone-driven preclinical development and regulatory review will be required to identify an appropriate chemotherapeutic to co-administer with the proposed therapeutic antibody in the proposed Phase 1b clinical trial.
- Feedback to the applicants from the FDA has been largely positive. However, reviewers were unclear whether the FDA concurred with the specific patient population that had been proposed for the Phase 1 CLL clinical trial and noted that this would be a critical question on which to gain early agreement.
Design and Feasibility
- The proposed dose escalation plan to establish the maximum tolerated dose (MTD) in a Phase 1a clinical trial in CLL is likely to be feasible, realistic and achievable with the proposed enrollment.
- Reviewers expressed concern that the scale of the current manufacturing plan might be insufficient to supply the amount of antibody required for the preclinical and clinical studies proposed. They encouraged the team to focus on process improvements and/or scale up to allow larger product lots and on the development of robust assays to demonstrate lot-to-lot comparability of the antibody.
- Reviewers stated it would be important for the team to develop pharmacodynamic assays for monitoring the clinical effects of the therapeutic antibody.
- CIRM should confirm the clinical trial operational details, and the investigators are recommended to carefully consider potential risks and put plans in place for their possible mitigation strategies. A plan is needed to address pharmacovigilance. It was recommended the investigators consider hiring an outside firm for product safety monitoring.
Principal Investigator (PI), Development Team and Leadership Plan
- The PI is a leader in the field of CLL and has assembled a strong and accomplished team. The site/disease leaders are well known and experienced.
- Reviewers noted that the clinician leading the CLL Phase 1 trial appears to have recently completed training and encourage close mentoring to assure success of the trial.
- The budget was adjusted to support those activities that fall within scope of the RFA with a direct project cost not to exceed $2,700,000 and total award cost not to exceed $4,179,600.
Collaborations, Assets, Resources and Environment
- The proposed clinical sites are highly capable and experienced in conducting similar Phase 1 clinical trials. Reported numbers of CLL patients referred to the primary clinical site yearly should support timely enrollment of the trial.
- The contract organizations that the applicants plan to use have appropriate and respected track records to support the antibody manufacture and CLL Phase 1 clinical trial.
There is a commitment for at least 25% leveraged funding from an external source, which will need to be confirmed by CIRM.
- Joy Cavagnaro