Patient-derived Xenografts of Hematological Malignancies Webinar Review

Share this Insight:     
Dr. Julia Schueler of Oncotest presented a webinar exploring her work with patient-derived xenografts (PDX) of hematological malignancies as model systems for drug development and tumor biology research. PDX models of hematological origin provide the same advantages as solid tumor PDX models, such as preserving tumor heterogeneity and the treatment sensitivity profile of the donor patient.

Platforms and Strategies for Hematological Patient-derived Xenografts

For successful development of hematological PDX, Dr. Schueler recommends the NOG mouse as an ideal host - it lacks T, B and NK cells - paired with one of two proven hematological tumor engraftment strategies:

  • Direct Bone Marrow Injection
    Bone marrow injection creates direct contact with normal microenvironment, which gives an advantage in engraftment. Engraftment is measured via flow cytometry.

  • Subcutaneous Injection
    While tumor load can be quantified with calipers, subcutaneous injection is an artificial system which does not reflect the disseminated nature of disease in the patient.
Pharmacological readouts for successful PDX engraftment vary by methodology. For direct bone marrow injections, success is measured against either flow cytometry of peripheral blood plus overall survival OR flow cytometry of peripheral blood plus flow cytometry of bone marrow and other organs at defined time points. Comparison of spleen size is another indicator; control spleens are much larger than those from successfully-treated mice.

Subcutaneous tumor models, on the other hand, can be assessed through caliper measurements and survival time.

As with solid tumors, establishment of hematological PDX models takes time. Individual tumors can take can take up to 200 days to engraft and expand in the initial engraftment step (P1). Growth of models in P2 tends to be faster, and passages beyond that tend to be similar to P2.

Available PDX Models

Oncotest has a variety of hematological PDX available, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), diffuse large B cell lymphoma (DLBCL) and non-Hodgkin's lymphoma (NHL).

Dr. Schueler reviewed some example characterization data for different acute myeloid leukemia PDX models. Engraftment can be followed serially via flow cytometry of peripheral blood. Other tissues can be examined after euthanasia, such as bone marrow or spleen. Interestingly, different AML models show different patterns of engraftment among particular tissues, but those patterns are stable within a model from passage to passage.

Example: Patient-derived Xenografts of DLBCL

Dr. Schueler described DLBCL models derived of human prostate carcinoma tissue. Lymphomas can sometimes develop in early PDX engraftments from EBV+ donors, arising from donor immune cells in the tumor tissue. In this case, the lymphomas that arose were characteristic of DLBCL and were further developed as hematological PDX.

In some cases, intravenous injection provided better engraftment compared to intratibial injection for this tumor type. An additional readout in this model is macroscopic examination of organs such as liver.

Dr. Schueler showed comparisons of DLBCL engraftment between NOD scid and NOG mice across four different PDX models. In this comparison, the NOG mouse provided superior performance. Two of the models did not engraft at all in NOD scid, but engrafted well in NOG. The other two could be engrafted in NOD scid, but the NOG provided higher take rate and more consistent growth in NOG compared to that NOD scid.