A Combination of Rituximab and Varlilumab Immunotherapy in Patients with B-cell Lymphoma

Inclusion Criteria: 1. Relapsed or refractory CD20+ B-cell lymphoma excluding chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). * High grade subgroup: Diffuse large B-cell lymphoma, FL grade 3b, transformed FL * Low grade subgroup: All low grade CD20+ B-cell lymphoma subtypes excluding CLL/SLL (e.g. FL grade 1,2 or 3a, MCL, LPL) 2. Disease must be recurrent or treatment refractory, and received at least one line of treatment. Rituximab-refractory participants are eligible for the entry into the study as long as the tumour expresses CD20. 3. At least one measurable lesion by CT scan (defined as \>1.5 cm in one axis) that is also easily accessible for biopsy. 4. Histological confirmation of relapse within 12 months of treatment. 5. 16 years of age or older. 6. Haematological and biochemical indices with the ranges shown below: * Laboratory Test Value required * Haemoglobin (Hb) ≥ 90 g/L (red cell support is permissible) * Absolute neutrophil count (ANC) ≥1.0 x 109/L (or ≥0.5 x 109/L if bone marrow involvement) G-CSF support is not permissible at screening. * Platelet count ≥75 x 109/L (or ≥30 x 109/L if bone marrow involvement) * Serum bilirubin ≤1.5 x upper limit of normal (ULN) unless raised due to Gilbert's syndrome in which case up to 3 x ULN is permissible * Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN unless raised due to hepatic involvement * Calculated creatinine clearance (Cockcroft-Gault formula) ≥30 ml/min (uncorrected value) 7. Ability to understand the purpose and risks of the study and provide written informed consent . 8. Willing and able to participate in all required evaluations and procedures in this study protocol. 9. Participants must be willing to participate in appropriate pregnancy prevention measures: * Women of childbearing potential who have a negative serum or urine pregnancy test during screening (within 14 days prior to the start of trial treatment) and agree to use one highly effective form of contraception combined with an effective form of contraception (see below) effective from the first administration of all study drugs, throughout the trial and for 12 months after last dose all study drugs are considered eligible. * Male participants with partners of child-bearing potential who agree to take measures not to father children by using one form of highly effective contraception from the first administration of all study drugs, throughout the trial and for 12 months after last dose of all study drugs are considered eligible. Male subjects must also refrain from donating sperm during this period. Contraception Contraception that is considered highly effective includes oral, injected or implanted progesterone-only hormonal contraception (with inhibition of ovulation); oral, intravaginal, or transdermal combined (oestrogen and progesterone containing) hormonal contraception (with inhibition of ovulation); an intra-uterine device (IUD); an intrauterine hormone releasing system (IUS); bilateral tubal occlusion; vasectomised partner or abstinence. Contraceptive methods considered to be effective include progesterone-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action; condom; cap, diaphragm or sponge with spermicidal gel. * Men with pregnant or lactating partners must be advised to use barrier method contraception (for example: condom plus spermicidal gel) to prevent exposure to the foetus or neonate. 10. Life expectancy ≥ 12 weeks. 11. ECOG performance status 0-2. Exclusion Criteria: 1. Known central nervous system involvement by lymphoma, that is not in remission, are excluded from the study. 2. History of other malignancy within the last 2 years except for: * Noninvasive malignancies such as adequately treated ductal carcinoma in situ of the breast, non-melanoma skin cancer or lentigo maligna, cervical carcinoma in situ and urothelial papillary noninvasive carcinoma or carcinoma in situ, and * Prostate intraepithelial neoplasia without evidence of prostate cancer. 3. Receiving treatment (or within a month of) with chemotherapy, immunotherapy or immunosuppressive agents. This includes any systemic steroids at dose exceeding 10 mg prednisolone (or other steroid equivalent) within 2 weeks prior to first dose of varlilumab. 4. Significant concurrent, uncontrolled medical condition that in the opinion of the Investigator contraindicates participation in this study. 5. Active and documented autoimmune disease (including, but not limited to, inflammatory bowel disease, coeliac disease, haemolytic anaemia, or immune thrombocytopenic purpura) prior to first dose of varlilumab. 6. Active infection requiring systemic therapy. 7. Women who are pregnant or lactating. 8. Serological positivity for Hepatitis B, C, or known HIV infection. As per standard of care the results of hepatitis serology should be known prior to commencement of immunochemotherapy. * Positive test results for chronic HBV infection (defined as positive HBsAg serology and positive HBcAb) will not be eligible. Participants with occult or prior HBV infection (defined as negative HBsAg and positive HBcAb) will not be eligible. Participants who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible. * Positive test results for hepatitis C (HCV antibody serology testing) will not be eligible. 9. Previous recipient of an allogeneic bone marrow transplant at any time. 10. Autologous bone marrow transplant within 100 days of first dosing. 11. Systemic radiation therapy within 4 weeks or prior focal radiotherapy within 2 weeks prior to first dosing. 12. Subjects known or suspected of being unable to comply with the protocol. 13. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia or certain Grade 1-toxicities, which in the opinion of the Investigator should not exclude the patient. 14. Uncontrolled congestive cardiac failure, cardiac ischaemia or cardiac arrhythmia. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to registration, congestive heart failure (NYHA III-IV). 15. Subjects with a known hypersensitivity to rituximab (≥Grade 3) or murine proteins, or any other excipients used in the formulation of rituximab.