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.

 

 

Prognostic Biomarkers in Diffuse Large B-cell Lymphoma

Jason Yonehiro, founder and CEO of CombImmune Inc., talked about diagnostic biomarkers in lymphoma and their application in clinical utility and drug discovery, at www.bio2devicegroup.org event.

Non-Hodgkin’s Lymphoma refers to any of a large group of cancers of lymphocytes (white blood cells) and is often marked by lymph nodes that are larger than normal, accompanied by fever and weight loss.  They can be aggressive or fast growing and indolent or slow growing.  NHL is steadily growing over past few years.  While there were 115,000+ cases of NHL in 2002, worldwide, over 140,000 cases of NHL are anticipated in 2019.  NHL is more common in women.

Currently R-CHOP, a combination therapy that adds the drug Rituximab, a monoclonal antibody to standard combination called CHOP, consisting of four chemotherapy drugs, is considered a standard regimen for Diffuse Large B-Cell Lymphoma, the commonest type of NHL.  Bone marrow transplant is considered to be the second line of treatment.  Rituxan can lead to serious, including fatal, adverse effects and not all patients respond to this mode of treatment.  There is a significant unmet need for effective therapies for treatment of T-cell lymphomas, said Yonehiro.  There are several drugs in the pipeline.  Avastin failed in the trials, Revlimid is showing promise, but likely to be pushed further in treatment paradigm and Rituxan continues to remain gold standard in treatment.  Rituxan is not cheap.  A 28 day regimen with Revlimid, costs up to $10,000.  Rituxan is expected to come off patent and price may come down but its efficacy remains the same.

Thus far, it has been observed that Diffused Large B Cell Lymphoma (DLBCL) patients do poorly with the current standard of care, the R-Chop therapy.  But there do not exist any molecular diagnostic tests that predict patient outcome.  About 75% of patients respond to the standard of care but about 30-40% of patients relapse and die within 5 years.  The challenge is to identify high risk patients who might benefit from more aggressive chemotherapy.  It is important to minimize overtreatment of all patients, offer more treatment options, individualize treatment plans, identify high risk patients, make better clinical assignment, and optimize treatment.

Studies indicate that distinct patterns of chromosomnal abnormalities characterize NHL and there is need to better understand how these differences impact the response to certain therapies, said Yonehiro.  The field of personalized medicine is growing.  About $9.7B went into this area but this is expected to double by 2017.  The tool currently used is International Prognostic Index or IPI.  It is a clinical tool developed to aid in predicting the prognosis of patients with aggressive non-Hodgkin’s lymphoma.  In addition to the Ann Arbor Stage, IPI added certain other factors deemed significant, including age, elevated serum LDH, performance status, and number of extranodal sites of diseases.  However, this tool does a poor job, said Yonehiro.

CombImmune’s mission is to utilize prognostic and predictive biomarkers that enhance understanding of immune dysfunction to tumor infiltration and combine that with therapeutics that restore immune function and destruction of the tumor.  CombImmune prognostic test is based on Two Gene Score (TGS) to identify high risk patients.  TGS + IPI give a significantly more accurate patient profile, said Yonehiro.  Originally, they developed a 300 gene assay and now it is distilled down to 2 genes.  TGS has been vetted through study of 692 patients and there is an ongoing 215 patients prospective study.  TGS is based on PCR (Polymerase Chain Reaction) standardized molecular diagnostic genetic technique.

Genomic information is critical to improving management of hematologic cancers, said Yonehiro.  Two Gene Test, based on LMO2 and CD 137 expressions are robust independent prognostic determinants in DLBCL.  All studies thus far clearly indicate that TGS and IPI capture more high risk patients than IPI alone.  The clinical utility and value would be in its ability to pick out patients in need of more aggressive therapy, while others are put on “wait and watch” list.  The talk was followed by Q&A.

English: Micrograph of a diffuse large B cell lymphoma, abbreviated DLBCL. Lymph node FNA specimen. Field stain. See also Image:Large b cell lymphoma – cytology small.jpg (Photo credit: Wikipedia)