Novel Approaches to Immune Therapy & Monitoring for non-Hodgkins Lymphoma

Dr. Russell Pachynsky, co-founder and CSO at CombImmune, spoke about their unique approach to immune therapy and monitoring for aggressive non-Hodgkins lymphoma patients, at www.bio2devicegroup.org event.  One of the clinical pain points with large B cell lymphomas, also called DLBCL is patients often do poorly after chemotherapy and current methods to identify high risk patients often lead to variations in patient outcomes, said Pachynsky.  Currently the standard method used is the IPI or International Prognostic Index but it is far from perfect where clinical outcomes are often discordant to risk prognosis. The IPI  is based on clinical assessments during the initial work-up of the patient which include age, Ann Arbor Stage, Serum LDH level, number of extranodal sites of the disease, and performance status.  Based on these, a patient receives the total score and higher the total score, higher the chances of them being at great risk of relapse and disease reoccurrence.  The challenge however is that the IPI does not capture the molecular heterogeneity of DLBCL.

English: Monoclonal antibodies for cancer. ADEPT, antibody directed enzyme prodrug therapy; ADCC, antibody dependent cell-mediated cytotoxicity; CDC, complement dependent cytotoxicity; MAb, monoclonal antibody; scFv, single-chain Fv fragment. (Photo credit: Wikipedia)

CombImmune offers a unique molecular diagnostic test that accurately identifies high risk patients.  After running FFPE tumor tissue through rt-PCR and based on certain algorithms the assay can identify patients who may be in need of more aggressive treatment.  Currently, first line therapy that is generally administered is R-CHOP therapy.  About 75% of patients with DLBCL respond to the standard R-CHOP therapy.  However, 50% of patients with non-Hodgkin’s lymphoma patients die despite receiving the therapy.  And there is nothing approved for maintenance therapy, for DLBCL patients.  Standard second line therapy consists of R-DHAP or R-ICE therapy and those who do not respond to that may go for bone marrow transplant.  Although it is more toxic, the Dose adjusted EPOCH or DA-R-EPOCH chemotherapy is currently in a Phase III CALGB trial 5303 (http://www.cancer.gov/clinicaltrials/search/view?cdrid=433265&version=HealthProfessional) vs R-CHOP in newly diagnosed DLBCL patients. If more found to be more efficacious, DA-R-EPOCH may offer DLBCL patients another option for first line therapy. There are also other combination therapies with R-CHOP in Ph2 and Ph3 trials including lenalidamide, bortezomib, GA-101, ibrutinib, idelalisib, and many others. According to Dr. Pachynski, there are over 100 programs currently evaluating new DLBCL therapies and it will be important to understand which patients will become Rituxan refractory and relapse earlier in their disease. All patients do not require this aggressive treatment and a molecular diagnostic assay will minimize the unneeded additional therapies and over treatment.

CombImmune’s unique assay the Two Gene Score or TGS has been validated in 692 DLBCL patients.  One of them is a measure of the tumor (LMO2) and one is a measure of immune response (CD137).  LMO2 and CD137 are robust, independent, and prognostic determinants of DLBCL.  This technology has come out of work at Ron Levy’s lab, at Stanford.  Compared to TGS the IPI captured only 7% of high risk patients, while the validation cohort, the TGS captured 28.5% of high risk patients.  Based on this test, high risk patients can be administered more aggressive first line of treatment, while wait and watch approaches can be taken with low risk patients.

Additionally, CombImmune’s TGS test is useful in monitoring and enhancing immune response to cancer.  Energizing the immune system to illicit a more robust response can be a key to more efficacy of treatment.  It is already known that new DLBCL patients have impaired immune mediated NK cell cytotoxicity and lower CD137 expression.  DLBCL patients have a compromised immune system, at the time of the diagnosis.  It is also known that increased tumor infilterating leukocytes are prognostic and predictive.  Clinical outcomes are generally good with increased counts, and poor, when lower.  It is also known that active monitoring of patient immune system may improve clinical outcomes.  The TGS diagnostic test and PF05082566 (anti CD137 mAB) can capture true high risk patients who are Rituximab non-responders.  Rx may play synergistic role with antibodies to stimulate CD137 expression in NK/T cells.  Sequential dosing of co-stimulatory agents have anti-cancer synergy.  Currently, there are a number of pathways and co-inhibitation therapeutics under investigation.  Many of them will likely increase CD137 expression.  Dr. Pachynski said, TGS is a powerful way to monitor immune response of the tumor.  The event was followed by Q&A.