A2B101-101: Obtaining Primary Solid Tumor Tissue from Subjects Having Primary Surgical Resection for Certain Tumor Types and Leukapheresis for CAR T-cell Therapy Manufacturing

Overview

About this study

The primary objectives for this study are: 

  • The percentage of subjects who can enroll on an A2 CAR T-cell therapy study within approximately 6 months of undergoing leukapheresis.
  • The percentage of subjects who can enroll on an A2 CAR T-cell therapy study within approximately 12 months of undergoing leukapheresis.
  • The percentage of subjects who can enroll on an A2 CAR T-cell therapy study within approximately 18 months of undergoing leukapheresis.
  • The percentage of subjects who can enroll on an A2 CAR T-cell therapy study within approximately 24 months of undergoing leukapheresis.
  • Percentage of screened subjects experiencing loss of heterozygosity of HLA-A*02.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria - Part 1:

  • Able to provide written informed consent.
  • Pathologically confirmed solid tumors; e.g., Colorectal Cancer (CRC), Non-Small Cell Lung Cancer (NSCLC), Pancreatic Cancer, Gastric and Esophageal Cancer, Ovarian Cancer, Mesothelioma, Breast Cancer, or Head and Neck Cancer and in the Investigator’s opinion the subject is high risk for incurable relapse within two years.
  • Age ≥ 18 years.

Exclusion Criteria - Part 1:

  • History of any of other malignancy in the past 5 years other than non-melanoma skin carcinoma, low grade localized prostate cancer, superficial bladder cancer, ductal carcinoma in situ (CIS) of the breast, CIS of the Cervix, or Stage I uterine cancer.
  • Prior allogeneic stem cell transplant.
  • Prior solid organ transplant.
  • In the investigator’s judgement, the subject is unlikely to complete all protocol required study visits, including hospitalization, study visits and procedures, and follow up visits, or comply with the study requirements for participation. 

Eligibility Criteria - Part 2:

  • Able to provide written informed consent.
  • Pathologically confirmed solid tumors; e.g., Colorectal Cancer (CRC), Non-Small Cell Lung Cancer (NSCLC), Pancreatic Cancer, Gastric and Esophageal Cancer, Ovarian Cancer, Mesothelioma, Breast Cancer, or Head and Neck Cancer and in the Investigator’s opinion the subject is high risk for incurable relapse within two years.
  • Age ≥ 18 years.
  • Subjects are germline HLA-A*02 heterozygous confirmed by HLA typing.
  • Primary tumor tissue showing LOH of HLA-A*02 by NGS.
  • Adequate bone marrow reserve, hematological, renal and hepatic function defined as: 
    • Hemoglobin > 9.0 g/dL;
    • ANC 800/µl;
    • Platelet count > 80,000/µl;
    • Serum Creatinine <1.5 x ULN;
    • Calculated Creatinine Clearance > 60 ml/min;
    • Total Serum Bilirubin < 2 x ULN;
    • ALT< 5 x ULN;
    • AST< 5 x ULN.
  • Eastern Cooperative Oncology Group (ECOG) performance status < 1.
  • Baseline oxygen saturation > 92% on room air.
  • No clinically significant pleural effusion.

Exclusion Criteria - Par 2:

  • History of any of other malignancy in the past 5 years other than non-melanoma skin carcinoma, low grade localized prostate cancer, superficial bladder cancer, ductal carcinoma in situ (CIS) of the breast, CIS of the Cervix, or Stage I uterine cancer.
  • Prior allogeneic stem cell transplant.
  • Prior solid organ transplant.
  • Presence of any indwelling catheter or drain (e.g., percutaneous nephrostomy tube, indwelling foley catheter, biliary drain, or pleural/peritoneal, pericardial catheter).  Ommaya reservoirs and dedicated central venous access catheters such as a Port-a-Cath or Hickman catheter are permitted.
  • Subjects who have received any cancer therapy (investigational agent or not), including but not limited to chemotherapy, small molecules, monoclonal antibodies, or radiotherapy (with bone marrow impact) within 3 weeks of planned leukapheresis or 5 half-lives, whichever is shorter.
  • Has a diagnosis of immunodeficiency or autoimmune disease requiring continued systemic therapy (e.g., monoclonal antibody therapy).
  • Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment necessitating specific treatment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to completion of antibiotic course).
  • Has known active central nervous system metastases. Subjects with previously treated brain metastases may participate upon sponsor agreement.
  • Known or suspected chronic, active Epstein Barr Virus (EBV).
  • Has known active history of or screened positive for Human Immunodeficiency Virus (HIV).
  • Has known active history of or screened positive for Hepatitis B (HBsAg positive) or C (anti-HCV positive).
  • Unstable angina, myocardial infarction, cardiac angioplasty or stenting, or any other significant cardiac disease within the last 6 months.
  • History of symptomatic deep vein thrombosis or pulmonary embolism within 6 months of enrollment.
  • Requires supplemental home oxygen.
  • Significant pulmonary disease (e.g., idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or obstructive pulmonary disease).
  • Females of childbearing potential who are pregnant or breastfeeding.
  • In the investigator’s judgement, the subject is unlikely to complete all protocol required study visits, including hospitalization, study visits and procedures, and follow up visits, or comply with the study requirements for participation. 

Eligibility last updated 11/10/21. Questions regarding updates should be directed to the study team contact.

 

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Julian Molina, M.D., Ph.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

855-776-0015

Jacksonville, Fla.

Mayo Clinic principal investigator

Hemant Murthy, M.D.

Contact us for the latest status

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

  • We describe an approach to cancer therapy based on exploitation of common losses of genetic material in tumor cells (loss of heterozygosity) (Basilion et al., 1999; Beroukhim et al., 2010). This therapeutic concept addresses the fundamental problem of discrimination between tumor and normal cells and can be applied in principle to the large majority of tumors. It utilizes modular activator/blocker elements that integrate signals related to the presence and absence of ligands displayed on the cell surface (Fedorov et al., 2013). We show that the targeting system works robustly in vitro and in a mouse cancer model where absence of the HLA-A*02 allele releases a brake on engineered T cells activated by the CD19 surface antigen. This therapeutic approach potentially opens a route toward a large, new source of cancer targets. Read More on PubMed
  • Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106× and 38×, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer. Read More on PubMed
  • Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT. Read More on PubMed
  • A powerful way to discover key genes with causal roles in oncogenesis is to identify genomic regions that undergo frequent alteration in human cancers. Here we present high-resolution analyses of somatic copy-number alterations (SCNAs) from 3,131 cancer specimens, belonging largely to 26 histological types. We identify 158 regions of focal SCNA that are altered at significant frequency across several cancer types, of which 122 cannot be explained by the presence of a known cancer target gene located within these regions. Several gene families are enriched among these regions of focal SCNA, including the BCL2 family of apoptosis regulators and the NF-kappaBeta pathway. We show that cancer cells containing amplifications surrounding the MCL1 and BCL2L1 anti-apoptotic genes depend on the expression of these genes for survival. Finally, we demonstrate that a large majority of SCNAs identified in individual cancer types are present in several cancer types. Read More on PubMed

Additional contact information

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