Rakhshanda Layeequr Rahman

Chimeric Antigen Receptor Engineering: A Right Step in the Evolution of Adoptive Cellular Immunotherapy

Cancer immunotherapy comprises different therapeutic strategies that exploit the use of distinct components of the immune system, with the common goal of specifically targeting and eradicating neoplastic cells. These varied approaches include the use of specific monoclonal antibodies, checkpoint inhibitors, cytokines, therapeutic cancer vaccines and cellular anticancer strategies such as activated dendritic cell (DC) vaccines, tumor-infiltrating lymphocytes (TILs) and, more recently, genetically engineered T cells. Each one of these approaches has demonstrated promise, but their generalized success has been hindered by the paucity of specific tumor targets resulting in suboptimal tumor responses and unpredictable toxicities. This review will concentrate on recent advances on the use of engineered T cells for adoptive cellular immunotherapy (ACI) in cancer.

The Role of Human Papilloma Virus (HPV) Infection in Non-Anogenital Cancer and the Promise of Immunotherapy: A Review

Over the past 30 years, human papilloma virus (HPV) has been shown to play a role in the development of various cancers. Most notably, HPV has been linked to malignant progression in neoplasms of the anogenital region. However, high-risk HPV has also been suggested to play a significant role in the development of cancers in other anatomic locations, such as the head and neck, lung, breast and bladder. In 2006, the first vaccine for HPV, Gardasil, was approved for the prevention of subtypes 6, 11, 16 and 18. A few years later, Cevarix was approved for the prevention of subtypes 16 and 18, the HPV subtypes most frequently implicated in malignant progression. Although increased awareness and vaccination could drastically decrease the incidence of HPV-positive cancers, these approaches do not benefit patients who have already contracted HPV and developed cancer as a result. For this reason, researchers need to continue developing treatment modalities, such as targeted immunotherapies, for HPV-positive lesions. Here, we review the potential evidence linking HPV infection with the development of non-anogenital cancers and the potential role of immunotherapy in the prevention and eradication of HPV infection and its oncogenic sequela.

Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer

OBJECTIVE Ovarian cancer is the most deadly gynecologic malignancy worldwide. Since the pathogenesis of ovarian cancer is incompletely understood, and there are no available screening techniques for early detection, most patients are diagnosed with advanced, incurable disease. In an effort to develop innovative and effective therapies for ovarian cancer, we tested the effectiveness of Galecti-3C in vitro. This is a truncated, dominant negative form of Galectin-3, which is thought to act by blocking endogenous Galectin-3. METHODS We produced a truncated, dominant-negative form of Galectin-3, namely Galetic-3C. Ovarian cancer cell lines and primary cells from ovarian cancer patients were treated with Galectin-3C, and growth, drug sensitivity, and angiogenesis were tested. RESULT We show, for the first time, that Galectin-3C significantly reduces the growth, motility, invasion, and angiogenic potential of cultured OC cell lines and primary cells established from OC patients. CONCLUSIONS Our findings indicate that Galectin-3C is a promising new compound for the treatment of ovarian cancer.

Anti-Galectin-3 Therapy: A New Chance for Multiple Myeloma and Ovarian Cancer?

Here we review the role of Galectins in the molecular pathogenesis of multiple myeloma and ovarian cancer, with a special focus on Glectin-3. Multiple myeloma is the second most common hematologic malignancy worldwide. Because the pathogenesis of multiple myeloma is still incompletely understood, there is no ultimately effective cure, and this cancer results fatal. Ovarian cancer is the most lethal gynecologic malignancy worldwide. Due to the lack of screening techniques for early detection, patients are mostly diagnosed with advanced disease, which results ultimately fatal. Multiple myeloma and ovarian cancer have different biologies, but they share a strong dependence on adhesion with extracellular matrix and other cells. Galectin-3 plays a key role in regulating such adhesive abilities of tumor cells. Here we discuss the outcomes and possible mechanism of action of a truncated, dominant negative form of Galectin-3, Galectin-3C, in these malignancies. Overall, we report that Galectin-3C is a promising new compound for effective adjuvant therapies in advanced, refractory multiple myeloma and ovarian cancer.

Effect of Paget's Disease on Survival in Breast Cancer: An Exploratory Study

OBJECTIVE To explore whether Pagets disease (PD) has an effect on outcome in patients with breast cancer. DESIGN Retrospective analysis of comprehensive pathology database, medical records, and slides of samples showing pathologic features. SETTING UMass Memorial Health Care. PATIENTS All patients with breast cancer and PD with records in a prospectively maintained database between January 1, 1990, and December 31, 2008, were identified. Each participant was matched (criteria: age within 5 years, year of treatment, and stage of breast cancer) with 2 controls (1:2 ratio). MAIN OUTCOME MEASURES Overall and disease-free survival were analyzed using Kaplan-Meier statistics and Cox proportional hazards modeling, accounting for matching in the latter analyses by using robust standard error estimates. RESULTS Mean (SD) follow-up was 47 (33) months. Treatment involved mastectomy in 29 (91%) PD vs 16 (25%) non-PD patients (P < .001), radiotherapy in 14 (44%) PD vs 53 (83%) non-PD patients (P < .001), and hormonal therapy in 14 (44%) PD vs 33 (52%) non-PD patients (P = .004). Biological markers were not significantly different except for ERBB2 (formerly HER2 or HER2/neu) overexpression in 14 (44%) PD vs 16 (25%) non-PD patients (P = .008). The PD group had an overall 5-year survival of 81.2% vs 93.8% of the non-PD group (Kaplan-Meier log-rank, P = .03). The unadjusted hazard ratio for the PD vs non-PD group was 5.31 (95% CI, 1.74-16.27; P = .003). The corresponding hazard ratio after adjusting for local and systemic treatment was 2.26 (95% CI, 0.46-11.06; P = .32). CONCLUSIONS These exploratory data show that PD may have a negative effect on breast cancer survival. This finding needs to be substantiated in larger data sets.

Cancer Testes Antigens in Breast Cancer: Biological Role, Regulation, and Therapeutic Applicability

Breast cancer remains one of the leading causes of death among women across the world. The last few decades have seen significant reduction in mortality owing to earlier detection and better adjuvant treatments that were developed based on clinical staging and morphological features. As these treatments have evolved, the heterogeneity of breast cancer poses a new challenge, since there is no standard gold-therapy suitable for all tumors of the mammary gland. Therefore, contemporary management and research efforts are directed toward specific prognostic and predictive molecular signatures that can guide targeted individualized therapy. The goal of ongoing research in this field is to identify specific molecular targets for developing novel therapeutic approaches. These targets can also serve to improve screening of breast cancer. This review focuses on the role of cancer testis antigens (CTAs) in breast carcinogenesis and explores the potential for development of targeted screening and therapeutic approaches. Normally found in the testes, these antigens are highly correlative with cancers of the breast, skin, and ovaries. These implications have been further corroborated through uncovering the interaction of CTAs with genes and proteins involved in tumor suppression and homeostasis like p53. There is some evidence that these genes can be targeted for early detection in addition to being candidates for cancer immunotherapy.

Stage migration with sentinel node biopsy in breast cancer

BACKGROUND Axillary staging provides the single most important piece of prognostic information in breast cancer patients. This retrospective study was performed to document the phenomenon of stage migration. METHODS Of 392 patients, 5 (1%) failed identification of sentinel lymph nodes (SLNs) and therefore underwent axillary lymph node dissection (ALND). Four patients (80%) had metastatic lymph nodes, 302 (77%) patients had negative SLNs, 47 (15%) underwent ALND, 85 (22%) had positive SLNs, 11 (13%) received adjuvant radiation treatment to the axilla, and 74 (87%) underwent completion ALND. RESULTS The median (quartiles) follow-up period was 29 months (19-46 mo). Twenty of 392 (5%) patients had disease relapse; 2 of which were local (.5%) and the rest were systemic. Earlier relapse was related significantly to lymph node status, tumor grade, and tumor size. SLN-negative patients who did not receive ALND had a relapse rate of 2.3% (6 of 256) compared with 0% in those who were truly negative based on confirmatory ALND. SLN-positive patients who did not receive ALND had a 9% (1 of 11) relapse rate. DISCUSSION The stage-matched pattern of relapse between SLN biopsy and ALND patients revealed lower relapse rates in SLN biopsy-staged patients, documenting the stage migration phenomenon.

Management of axilla in breast cancer - The saga continues.

Prospective trials investigating the accuracy of SLNB for cN0 (primary surgical therapy) and cN1 patients (neoadjuvant chemotherapy) have not utilized likelihood ratios (LR) to assess the impact of false negative SLNB. This review evaluates the evidence on accuracy of SLNB using STARD and QUADAS-2 (revised) criteria for patients undergoing primary surgical therapy and primary chemotherapy. It utilizes the: (i) Reported rates for pre-test probabilities of node positive disease from Surveillance, Epidemiology, and End Results (SEER) database for the cN0 patients (primary surgical therapy) for each T stage; calculates the negative LR from cumulative evidence; and uses the Bayesian nomogram to compute the post-test probability of missing the metastatic axillary node based on negative SLNB. (ii) Reported rates of complete axillary response in ACOSOG-Z1071 trial for cN1 patients to calculate the pre-test probabilities of residual nodal disease for each biological tumor sub-type; calculates the negative LR from ACOSOG-Z1071, and SENTINA trial data; and uses the Bayesian nomogram to compute the post-test probability of missing the residual metastatic axillary node based on negative SLNB. For cN0 disease, the odds of missing axillary disease based on negative SLNB for each T stage are: T1a = 0.7%; T1b = 1.5%; T1c = 3%; T2 = 7%; T3 = 18%. For cN1 disease, the odds of missing residual axillary disease based on negative SLNB for each biological subtype are: HER2neu+ = 8%; Triple negative = 15%; ER+/PR+/HER2neu- = 45%. Negative LR is more accurate and superior to false negative rate for determining the clinical utility of SLNB by taking into account the changing pre-test probability of disease.

Chemoprevention of Breast Cancer: The Paradox of Evidence versus Advocacy Inaction

Women who are at high risk of breast cancer can be offered chemoprevention. Chemoprevention strategies have expanded over the past decade and include selective receptor modulator inhibitors and aromatase inhibitors. Physicians are expected to provide individualized risk assessments to identify high risk women who may be eligible for chemoprevention. It is prudent that physicians utilize a shared decision approach when counseling high risk women about their preventive options. Barriers and misperceptions however exist with patient and physician acceptance of chemoprevention and continue to impede uptake of chemoprevention as a strategy to reduce breast cancer risk. Programs to increase awareness and elucidate the barriers are critical for women to engage in cancer prevention and promote chemoprevention adherence.

Protective properties of n-3 fatty acids and implications in obesity-associated breast cancer

Obesity is well documented as a risk factor for developing breast cancer, especially in postmenopausal women. Adipose tissue in the breast under obese conditions induces inflammation by increasing macrophage infiltration and pro-inflammatory cytokines that in turn up-regulates genes and signaling pathways, resulting in increased inflammation, cell proliferation and tumor growth in the breast. Due to their potent anti-inflammatory effects, n-3 polyunsaturated fatty acids (n-3 PUFA) are a promising and safe dietary intervention in reducing breast cancer risk. Here, we briefly review current status of breast cancer and its relationship with obesity. We then review in depth, current research and knowledge on the role of n-3 PUFA in reducing/preventing breast cancer cell growth in vitro, in vivo and in human studies, and how n-3 PUFA may modulate signaling pathways mitigating their effects on breast cancer development.