Associate Research Scientist
Clinical Development and Product Supervisor

Cancer Immunotherapy Laboratory and the Blood and Stem Cell Transplantation Programs
Adele R. Decof Cancer Center
Roger Williams Medical Center-
North Campus G05
825 Chalkstone Avenue
Providence, RI  02908
(401)456-5783 tel.
(401)456-2398 fax

pdavol@rwmc.org

Ongoing Breast Cancer Immunotherapy Clinical Trials at RWMC:

Phase I/II Study of Immunotherapy With Armed Activated T Cells, Interleukin-2, and Sargramostim (GM-CSF) in Women With Stage IV Breast Cancer

Phase I/II Study of Sequential Paclitaxel, Doxorubicin, and Cyclophosphamide Followed By Immunotherapy With Activated T Cells, Interleukin-2, and Sargramostim (GM-CSF) in Women With High-Risk Stage II or III Breast Cancer

Phase I/II Study of High-Dose Chemotherapy Followed By Autologous Peripheral Blood Stem Cell Transplantation and Immunotherapy With Activated T Cells, Interleukin-2, and Sargramostim (GM-CSF) in Patients With Stage IIIB or IV Breast Cancer or Other Solid Tumors

Ongoing Prostate Cancer Immunotherapy Clinical Trials at RWMC:

Phase I/II Study of Immunotherapy With Armed Activated T Cells, Interleukin-2, and Sargramostim (GM-CSF) in Men with Hormone Refractory Prostate Cancer

Non-Hodgkin's Lymphoma (NHL)  Immunotherapy Clinical Trials at RWMC:

Immune Consolidation with Activated T Cells Armed with OKT3 x Rituxan (anti-CD3 x anti-CD20) Bispecific Antibody after Peripheral Blood Stem Cell Transplant for High Risk CD20+ Non-Hodgkin’s Lymphomas

Immune Consolidation with Allogeneic Activated T Cells Armed with OKT3 x Rituxan® (anti-CD3 x anti-CD20) Bispecific Antibody (CD20Bi) after Allogeneic Peripheral Blood Stem Cell Transplant for High Risk CD20+ Non-Hodgkin’s Lymphomas (Phase I).

Non-Small Cell Lung Cancer Immunotherapy Clinical Trial at RWMC:

Treatment of Non-Small Cell Lung Cancer (NSCLC) with OKT3 x Erbitux Armed Activated T Cells, Low Dose I­L-2, and GM-CSF (Phase I).

Immunotherapy Clinical Trial for Pancreatic Cancer, Colon Cancer, Head and Neck Cancer, and other EGFR+ Solid Tumors:

Treatment of EGFR+ Solid Tumors with OKT3 x Erbitux Armed Activated T Cells, Low Dose I­L-2, and GM-CSF (Phase I).

Ovarian Cancer Immunotherapy Clinical Trials:

Phase I/II Study of High-Dose Chemotherapy Followed By Autologous Peripheral Blood Stem Cell Transplantation and Immunotherapy With Activated T Cells, Interleukin-2, and Sargramostim (GM-CSF) in Patients With Stage IIIB or IV Breast Cancer or Other Solid Tumors

Treatment of Recurrent Ovarian Cancer with OKT3 x Herceptin Armed Activated T Cells, Low Dose IL-2, and GM-CSF (Phase I).

For more information, please visit the Cancer Immunotherapy Program website.

Targeting Cancer through Unique Cell Surface Receptors and Their Signaling Pathways: Therapeutic and Prognostic Applications

Cancer cells often express certain molecules (antigens, growth factor/cytokine receptors, etc.) on their surfaces that are different or in greater number than expressed on normal cells. With normal cells, growth factors bind to growth factor receptors and generate an intracellular signaling cascade of molecular reactions that results in cell proliferation. Many cancer cells over-express these growth factor receptors and their ligands compared to normal cells.  As a result, the growth factor receptor signaling-transduction pathways are aberrantly activated in many cancers, including melanoma, glioblastoma, and often in carcinoma of the ovary, prostate and breast.  Over the years, my research has focused on exploiting the receptors and signaling pathways of cancer cells for both therapeutic and prognostic applications.

 Targeting Receptors for Cancer Therapy 

My early research focused on therapeutic applications whereby antibodies or ligands that specifically bind to the receptors of cancer cells are linked to toxic drugs in order to deliver them directly into cancer cells.  This type of therapeutic strategy allows specific delivery of the toxin to cancer cells while sparing the patient the non-specific toxicities frequently associated with conventional chemotherapeutic agents. Though an effective means for inhibiting the growth of cancer cells, adverse side-effects associated with the toxins often produced limitations for this therapeutic approach, as well. 

An alternative approach currently undergoing Phase I/II clinical trials for Stage IV breast cancer and other advanced cancer patients at Roger Williams Medical Center in Providence, RI, is the strategy of utilizing components of the patient’s own immune system in place of toxins. By cross-linking T cell receptors (TCR) of T lymphocytes (cells of the immune system involved in defending against cancer) obtained from the cancer patient with anti-CD3 monoclonal antibody, we create “activated” T cells (ATC) that upon infusing back into the patient, boosts the patient’s immune response by inducing T cell proliferation and cytokine synthesis for immune-mediated tumor cell killing. Building further upon this strategy, we have “armed” these patient-donated T cells with OKT3 (anti-CD3) x Herceptin bispecific antibody (Her2Bi), thus creating an artificial TCR on the patient’s ATC that redirects immunocytotoxicity specifically to breast cancer tumors and metastatic cells that are positive for the Her2/neu receptor (a receptor tyrosine kinase over-expressed in some breast as well as prostate and pancreatic cancers). The Her2Bi persists on ATC and mediates multiple rounds of redirected non-MHC restricted cytotoxicity directed at Her2/neu positive tumor targets for 20 days or more, while producing no non-specific toxicities to the patient.  Therefore, armed ATC may safely function not only as Her2-specific cytotoxic T lymphocytes when re-infused back into the breast cancer patient, but may also divide and secrete cytokines and chemokines after binding to tumors; thus potentially leading to increased numbers of armed ATC directed at Her2, as well as recruiting the endogenous T cells and antigen-presenting cells (APCs) of the patient to the sites of the cancer. 

 Receptor Signaling Pathways and Breast Cancer Prognosis

     Nearly 200,000 women in America are diagnosed with invasive breast cancer yearly, most presenting with early stage, node negative disease. Although only a small percentage of these patients have aggressive disease that will recur after removal of the primary tumor, most relapsed patients succumb to their disease.  Unfortunately, prognostic markers currently accepted for clinical use, such as nodal status, disease stage, tumor stage, histologic grade, and steroid receptor status, do not adequately identify which early stage, node-negative patients are at low or high risk for disease recurrence.  For this reason, most patients choose to receive adjuvant therapies.  One urgent need, therefore, is for better prognostic indicators for early stage, node negative patients. Additionally, patients with node positive, non-metastatic disease comprise another important group whose clinical management could benefit from additional prognostic markers that are independent of those currently in use.

Alterations in the axes of several growth factor receptors including receptors for insulin-like growth factors (IGF), epidermal growth factors (EGF), transforming growth factor-alpha (TGF-a) and fibroblast growth factors (FGF) have important implications for discerning tumors with an aggressive phenotype. In particular, autocrine and paracrine growth factor ligands associated with these receptors appear to play a key role in emergence of treatment resistant tumor cells. Because of the heterogeneity of tumors as well as the ubiquitous nature of growth-factor receptors and their ligands, limitations to the use of receptor/ligand expression as prognostic indicators are expected. Indeed, this has particularly been true of Her2/neu (Her2) receptor analysis in breast cancer patients in which up to only 30% of breast cancers are associated with over-expression of Her2 and of these, only one-third demonstrate activated Her2.

An alternative method is to examine markers that are downstream of receptor activation in the signaling cascade, and therefore, will provide a more general indicator of receptor activation. To this end, we have concentrated on the p52/p46 Shc signaling protein (which links growth-factor receptor signaling to the Ras, Rac(?), JNK, & Myc pathways). Activated Shc signaling proteins are implicated in many pathways associated with aggressive disease, and many breast cancer cell lines derived from highly aggressive tumors contain high levels of activated, tyrosine phosphorylated (PY)-Shc (the 46- and 52-kDa isoforms) relative to levels of an inhibitory 66-kDa Shc isoform.  Our aims of study, therefore, have been driven by the hypothesis that high amounts of PY-Shc relative to the 66-kDa Shc isoform in patient primary breast tumors would serve as a marker for aggressive neoplasms.  We have developed an antibody that specifically recognizes only PY-Shc and another that recognizes only the inhibitory p66-Shc. By performing retrospective immunohistochemical analyses on the primary tumors of patients who were diagnosed with either node negative or node positive, non-metastatic breast cancer, we have found that those patients who score a “high” Shc Ratio have a 10-fold greater risk for developing breast cancer relapse after initial treatment compared to patients that score a low Shc Ratio.  Subsequent to our studies, OncoPlan™ (Frackelton & Davol, patent pending) has been licensed for clinical development to Catalyst Oncology.  In further validation testing, OncoPlan™ has proven to be a useful indicator for poor clinical prognosis and therefore, may serve as a guide to clinicians for developing aggressive treatment protocols for early-stage cancers demonstrating high ratios of PY-Shc expression to p66-Shc expression.

Recent abstracts: