As we move from monotherapies to combinations in the immuno-oncology space, we start to see some intriguing ideas being explored from additional checkpoints to vaccines to neoantigens to immune agonists to oncolytic viruses. There are numerous ways to evaluate how to boost or jumpstart more immune cells upfront in the hope of seeing better efficacy.
One way to do this is to better understand the tumour microenvironment.
Wall of people at ASH16 in San Diego
If we know what’s wrong under the hood, we might be better able to make the immune system get going… more gas, faulty starter motor, dead battery, loose wire, broken fan belt? All these things and more might be a problem so you can see that diagnosing the issue up from from basic and translational work might be instructive for clinical trials.
If you don’t know what problem you’re trying to fix or repair then you might as well be throwing mud at the wall. Just as we don’t expect a car mechanic to suggest changing the battery or starter-motor without first diagnosing the issue, so understanding the tumour microenvironment in each different cancer or disease might also be a helpful strategy.
At the recent American Society of Hematology annual meeting (#ASH16), there was a fascinating sceintifc workshop that focused on this very concept – what’s going on under the hood and how do we go about fixing it?
Here we explore these ideas via an interview with a thought leader and specialist in the field. What he had to say was very interesting and candid indeed.
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Over the last two years there has been a lot of focus on indolent lymphomas (iNHL) and chronic lymphocytic leukemia (CLL) with numerous new targeted therapies being tested in clinical trials including ibrutinib (Imbruvica), idelalisib, ABT–199 and IPI–145 to name a few.
What about diffuse large B cell lymphomas (DLBCL) though? These are much more aggressive and generally have a poorer prognosis than indolent lymphomas.
Standard treatment upfront for DLBCL is R-CHOP i.e. rituximab plus chemotherapy i.e. cyclophosphamide (C), doxorubicin hydrochloride (H), vincristine/Oncovin (O) and prednisone (P). R-CHOP is usually given in cycles every 3 weeks (R-CHOP21) and most patients receive between 3 and 8 cycles. Sometimes R-CHOP is given every two weeks (R-CHOP14) in a more intensive fashion, although the dose dense regimen has not been shown to improve progression-free survival (PFS). In younger patients with a high disease burden, etoposide is sometimes added to the chemotherapies, making the regimen R-EPOCH.
One of the biggest challenges with treating this disease is that some 40% of patients do not respond to salvage therapy after initial treatment with R-CHOP, making it an area of hugh unmet medical need.
The good news is that there were a number novel and interesting therapies in development with promising data in Chicago. Previously, we discussed the promising data from the antibody drug conjugates (ADCs) from Genentech and Seattle Genetics, including SGN-CD19A, polatuzumab vedotin and pinatuzumab vedotin. This article takes a look at other therapies in development for DLBCL, including TKIs and the promise of some of the earlier therapies in the clinic:
Agents mentioned: lenalidomide (Revlimid), GS–9973, cerdulatinib (PRT062070), IMGN529, TAK659, selinexor, ND–2158
Companies mentioned: Celgene, Gilead, Roche/Genentech, Portola, Immunogen, Millennium/Takeda, Karyopharm, Nimbus Discovery
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Originally, I was thinking of doing an in-depth review of lymphomas i.e. non-Hodgkin’s lymphoma (NHL), which involve 85% of lymphomas and Hodgkin’s lymphoma (HL), which take up the remaining 15%. This topic, however, has been largely done to death already.
There are are some very useful sources of carefully curated content that I enjoy following every year and in this post I’m going to direct you to some of those and highlight where I think the critical topics are in lymphomas.
Companies mentioned: Roche, GSK, AbbVie, Pharmacyclics, Gilead, Infinity, Seattle Genetics
Drugs mentioned: Rituxan, Arzerra, Gazyva, ABT-199, ibrutinib, idelalisib, IPI-145, Adcetris