Novel therapeutic agents for B-cell lymphoma: developing rational combinations -
Blood 2011 Full text: http://bit.ly/i7c7qs

Fairly technical but a useful review of the landscape, providing summary discussion of 1) the class of drug, the 2) mechanism of activity, 3) its use so far in lymphoma, and 4) toxicities.

Monoclonal antibodies (mAbs)

mAbs (monoclonal antibodies) are proteins that binds to molecules
(antigen receptors) on cells, such as cd20 (the target of Rituxan) 

 See also pathologyoutlines.com

CD overview - Clusters of Differention cellular-immunity

See also LookUp Table

Next Generation anti-CD20 mAbs

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CD20 type II antibody (GA-101)

Indication: Lymphomas, b-cell (expressing CD20)

Compared to existing CD20 antibodies GA101 represents a novel, third generation antibody with significantly enhanced efficacy in a variety of in vitro and in vivo preclinical models. GA101 constitutes the first type II CD20 antibody successfully engineered for increased ADCC.

ASH 2010 clinical report http://ash.confex.com/ash/2010/webprogram/Paper32143.html

Overview of technology by sponsor: PDF 

CD20 antibody - next generation 
(Ofatumumab /Arzerra (r) )

Indication: Lymphoma/CLL, b-cell expressing CD20

NEWS: FDA conditional approval for refractory CLL

(HuMax-CD20™) is a fully human, high-affinity antibody targeted at the CD20 molecule in the cell membrane of B-cells.

Also see Report on Clinical responses Feb 2008 

CD20 antibody - next generation
(Veltuzumab / Immu-106 / Ha20)

Indication: Lymphomas, b-cell (expressing CD20)
 
"A [humanized anti-CD20] monoclonal antibody that is being studied in the treatment of refractory B-cell non-Hodgkin's lymphoma." Source
  
Data: Phase I/II Results  ASH 2006 

CD20 antibody  - first generation
(Rituximab / Rituxan / Mabthera)

APPROVED for CD20 lymphomas See Rituxan

Indication: Lymphoma/CLL expressing cd20 (APPROVED)
 
Rituxan (formerly C2B8) See Rituxan

Not Recruiting

Active - not recruiting: CD20 antibody - next generation (AMME-133v)

Indication: Lymphomas, b-cell (expressing CD20)
 
AME-133v is hypothesized to result in an anti-CD20 therapy with greater potency and efficacy in all patients.

Other CD-targeting Mabs

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Description

CD4 antibody (Zanolimumab)

Indication: Lymphoma, T-cell
 
(Zanolimumab) HuMax-CD4® is a human antibody being developed under an agreement with Serono and is currently in Phase III development for cutaneous T-cell lymphoma (CTCL) and in Phase II for non-cutaneous T-cell lymphoma.

Zanolimumab Shows Long-Lasting Responses in T-Cell Lymphoma Patients Docguide

Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma http://bloodjournal.hematologylibrary.org/content/109/11/4655.long

CD22 antibody
(Epratuzumab)

Indication: Lymphoma, CD22 positive
 
an anti-CD22 humanized monoclonal antibody

CD23 antibody
(Lumiliximab)

Indication: Lymphomas (expressing CD23) 
 
CD23, the low-affinity immunoglobulin (Ig)E receptor (FcepsilonRII), is widely distributed on the surface of various human cells. CD23 mediates numerous IgE-related immune responses  Source  | Background article

CD30 antibody
(SGN-30)

Indication: Lymphoma expressing CD30, such as Hodgkins
 
a monoclonal antibody that targets the CD30 antigen, which is expressed on hematologic malignancies including Hodgkin's disease and some T-cell non-Hodgkin's lymphomas. Seattle Genetics is conducting ongoing phase II clinical trials of SGN-30 as a single agent in systemic ALCL and cutaneous ALCL." Press release

CD37 antibody 
(IMGN529)

IMGN529 retains these antibody-dependent anticancer activities, and also has the mechanism of action of a TAP compound: targeted delivery of the potent DM1 agent to the tumor cells. In preclinical testing, IMGN529 was found to have greater anticancer activity than its antibody component alone.

CD37 single-chain polypeptide antibody (TRU-016)

"A recombinant single-chain polypeptide engineered to exhibit the full binding and activity of an anti-CD37 monoclonal antibody with potential immunostimulatory and antineoplastic activities.  http://www.cancer.gov/drugdictionary/?CdrID=589521

RESULTS: A Phase 1 Trial of TRU-016, An Anti-CD37 Small Modular Immunopharmaceutical (SMIPTM) Protein in Relapsed and Refractory CLL: Early Promising Clinical Activity 
http://bit.ly/TRU-016

 

CD40 Antibody (dacetuzumab)

Indication: Lymphomas, b-cell (expressing CD40) 

CD45 Antibody

Indication: Lymphomas, b-cell (expressing CD45) 

CD47 Antibody - PRECLINICAL

Indication: Lymphomas, b-cell, and AML

We will be watching for clinical phase testing of this new target.

Blockade of CD47 signaling by a monoclonal antibody can eliminate NHL cells by enabling phagocytic engulfment. Here we investigate the therapeutic potential of an anti-CD47 antibody alone and in combination with rituximab for the treatment of NHL. We predict that the combination of anti-CD47 antibody and rituximab through utilization of two independent antibody mechanisms will result in synergistic phagocytosis and elimination of NHL cells.

(preclinical)

CD52 antibody
(Campath (r) / alemtuzumab)

APPROVED for CLL

Indication: Lymphomas: CLL 
 
"A humanized monoclonal antibody directed against the CD52 antigen with promising therapeutic effects in patients with small cell lymphocytic non-Hodgkin's lymphomas (NHL) of B- and T-cell type."

CD70 antibody
(MDX-1411)

Indication: Lymphomas and CLL

Cellular expression: Activated T and B cells, and macrophages

a fully human monoclonal antibody that targets the CD70 receptor, which is a member of the tumor necrosis factor (TNF) family.

CD74 antibody
(Milatuzumab / hLL1)

Indication: b-cell lymphomas

Immunomedics Patents Internalizing Anti-CD74 Antibodies  Reuters 

CD80 antibody
(IDEC-114 / Galiximab)

Indication: Lymphomas
 

Other Antibodies

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PD-1 (P7) receptor antibody
(CT-011)

Indication: Lymphomas

“One of the leading causes for immune suppression in cancer patients was suggested to be associated with the elevated expression of PD-L1 (B7-H1) at tumor-involved sites, resulting in local suppression and apoptosis of tumor-infiltrating effector lymphocytes.

Animation by sponsor:
How CT-011 thought to work? http://bit.ly/jWVQ8S 

Safety & efficacy study clincancerres.aacrjournals.org
2011 Clinical report - media press release: globes.co.il/

KW-0761 antibody directed against CCR4 (CD194) on T-cells

Indication:  The target of KW-0761 is a molecule that may be over-expressed on adult T-cell lymphoma (ATL) and peripheral T-cell lymphoma (PTCL) cells.

Mechanism of action:

KW-0761 selectively binds to and blocks the activity of CCR4, which may inhibit CCR4-mediated signal transduction pathways and, so, chemokine-mediated cellular migration and proliferation of T cells, and chemokine-mediated angiogenesis.

=> Translation: an antibody binding to this target might stop processes within t-cells that support malignant behavior – excessive growth of the abnormal cells and blood supply to these cells.

In addition, this agent may induce antibody-dependent cell-mediated cytotoxicity (ADCC) against CCR4-positive T cells.

=>Translation: this antibody (like Rituxan) might lead to the killing of the cells this antibody binds to – by the immune system.

CCR4 is expressed on the surfaces of some types of T cells, endothelial cells, and some types of neurons.

… => Which helps to predict the kinds of toxicities to monitor for.

 

Mabs Coupled with Toxins or Chemo

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Description

 CD19 and CD22 antibody, + immunotoxin (DT2219ARL)

Indication: Lymphomas, b-cell (expressing CD19 and CD22) 

"A bispecific ligand-directed toxin (BLT) called DT2219ARL consisting of two scFv ligands recognizing CD19 and CD22 and catalytic DT390 was genetically enhanced for superior in vivo anti-leukemia activity. Technical background: ncbi.nlm.nih.gov

CD19 antibody + cytotoxic - maytansinoid (SAR3419)

Indication: Lymphomas, b-cell - expressing cd19

an immunoconjugate consisting of an anti-CD19 monoclonal antibody conjugated to the maytansinoid DM4, a derivative of the cytotoxic agent maytansine (DM1), with potential antineoplastic activity.

Details:  http://www.cancer.gov/ 

Phase I/II report - ASCO 2011:  http://abstract.asco.org/AbstView_102_78324.html 
Press release of same: http://bit.ly/m0CxxM

CD22 antibody + immunotoxin
(CAT-8015)
 

Indication: b-cell lymphomas 

an optimized version of  CAT-3888 with increased affinity for CD22. CD22 is a cell surface receptor expressed in a wide variety of B-cell malignancies. The anti-CD22 immunotoxin CAT-8015 comprises a dsFv that targets the CD22 receptor, fused with a specifically engineered toxin molecule that minimizes non-targeted toxicity, resulting in a highly specific, highly potent therapeutic molecule. The molecule acts by releasing the toxin intracellularly (within the cell), after the whole immunotoxin has been internalized via the CD22 receptor." 

CD22 antibody + cytotoxic - calicheamicin (CMC-544 /
Inotuzumab Ozogamicin)

Indication: Lymphoma, b-cell - CD22 positive

a humanized anti-CD22 antibody conjugated to calicheamicin, a cytotoxic agent. IO targets CD22, which is expressed in the majority of B-cell NHL.
 
a CD22-targeted immunoconjugate of calicheamicin and exerts a potent cytotoxic effect against CD22⁺ B-cell lymphoma  http://clincancerres.aacrjournals.org/cgi/content/full/12/1/242

CMC-544 + Rituximab In Relapsed DLBCL Patients Followed by Stem Cell Transplantation: Preliminary Safety and Efficacy
http://ash.confex.com/ash/2010/webprogram/Paper33326.html

  

CD22 antibody + toxic protein dgA-RFB4
(Mono-dgA-RFB4 )

Indication: Lymphomas, b-cell expressing cd22

Scant background information so far; one trial, completed with no found reports of outcomes

CD25 antibody + immunotoxin
(LMB-2 immunotoxin)

Indication: Lymphomas, b-cell (expressing CD25) 

"an antibody Fv fragment fused to truncated Pseudomonas exotoxin."  ncbi.nlm.nih.gov

CD30 antibody + antitubulin agent
(SGN-35 / brentuximab vedotin)

Indication: Lymphoma expressing CD35, such as ALCL
 
"Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) comprising an anti-CD30 antibody linked to a potent, synthetic drug payload, monomethyl auristatin E (MMAE)"

NEW FDA Advisor Panel Backs Accelerated Approval of Brentuximab for Hodgkins Lymphoma and ALCL http://bit.ly/pr3er1

IL-2 antibody + toxic protein
(Ontak / Denileukin diftitox)

Indication: Lymphoma (APPROVED for t-cell lymphomas)
 
a toxin fusion protein. The IL-2 portion of the molecule targets the lymphoma cells by binding to the IL-2 receptor on the plasma membrane, and upon endocytosis, the diphtheria toxin is delivered to the lymphoma cells.   www.ncbi.nlm.nih.gov

Bi-specific mAbs
 binds two antigens on target cells

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Description

CD22 antibody
(4g7xH22)

DORMANT - study completed, no results posted.

Indication: In Patients With Refractory or Relapsed Non-Hodgkin's Lymphoma or Chronic Lymphocytic Leukemia (CLL)

Intravenous Bispecific Antibody (4G7XH22) 

 CD19 AND CD3 antibody
(BiTe / Blinatumomab / MT103)

Indication: Lymphomas, b-cell (expressing CD19) 
 
Binds to B-cells and T-cells Details : http://www.ncbi.nlm.nih.gov/pubmed/17083975

Also see: News item on clinical responses Feb 2008

Radio-labeled mAbs 
(See also Radioimmunotherapy - RIT)

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  CD22 + fractionated Yttrium 90
 (90Y-hLL2 IgG / epratuzumab tetraxetan)

Indication: Lymphomas expressing CD22
 
using epratuzumab (cd22 antibody) to deliver radiation directly to lymphoma cells in small fractions (fractionated doses" Source

High Rates of Durable Responses With Anti-CD22 Fractionated Radioimmunotherapy: Results of a Multicenter, Phase I/II Study in Non-Hodgkin's Lymphoma http://jco.ascopubs.org/content/28/23/3709.abstract

CD20 antibody + radiation emitting particle - iodine 131
 (Bexxar (r) / Tositumomab, Iodine I 131)

APPROVED for relapsed indolent b-cell lymphoma. See Bexxar

See also Comparing Properties of Bexxar and Zevalin

CD20 antibody + radiation emitting particle - Yttrium 90
 (Zevalin (r) / Ibritumomab tiuxetan)

See also Comparing Properties of Bexxar and Zevalin
 

Go to studies
Clinicaltrials.gov

Other antibody + radiation emitting particle  (Various)

Non-cd20 antibodies with radioisotopes in clinical phase study - more than you might expect.

Apoptosis 

Apoptosis: means programmed cell death - a normal process by which the body rids itself of old, unneeded, or damaged cells.  This event is similar to what we see in a sun burn - when over-exposed skin cells die and peel. Cancer cells have turned on pathways that resist this process, which can be targeted by new drugs.

"Evasion of apoptosis is a hallmark of cancer (1). Cancer cells must overcome a continual bombardment by cellular stresses such as DNA damage, oncogene activation, aberrant cell cycle progression, and harsh microenvironments that would cause normal cells to undergo apoptosis. One of the primary means by which cancer cells evade apoptosis is by up-regulation of the prosurvival Bcl-2 family proteins such as Bcl-2, Bcl-xL, and Mcl-1 (1, 2). Thus, a variety of approaches to target these oncoproteins have been pursued to restore the natural process of programmed cell death (3).  - cancerres.aacrjournals.org/

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Description

Inhibitor of bcl-2 family of proteins - ABT-263

Orally Bioavailable, Small molecule

Indication: Lymphoma
 
"ABT-263 is an orally bioavailable small molecule inhibitor of Bcl-2 family proteins "   ABT-263 in subjects with refractory or relapsed lymphoid malignancies.  ASCO 2009

Inhibitor of NAD 
(nicotinamide adenine dinucleotide)

Continuous IV infusion

Indication: t-cell lymphomas
 
"APO866 inhibits intracellular NAD, which essential for cell survival. NAD depletion resulting from APO866 treatment elicits tumor cell death."  http://bloodjournal.hematologylibrary.org

Inhibitor of bcl-2 family of proteins - AT101 (gossypol)

Indication: Lymphomas
 
gossypol - a naturally occurring polyphenolic compound derived from cottonseed and was initially evaluated as an anti-fertility agent. Gossypol induces apoptosis in tumor cells with high Bcl-X_L and/or Bcl-2 expression levels, leaving normal cells with low expression levels (e.g. fibroblasts, keratinocytes) relatively unaffected [16].  http://www.ro-journal.com/content/4/1/47

Pan-Bcl-2 Inhibitor | Background article PDF  | ASCO clinical report | Safety article: ascentatherapeutics.com  .pdf  

Inhibitor of the protein kinase Cbeta isozyme - Enzastaurin  (LY317615)

Indications: Lymphoma

an acyclic bisindolylmaleimide, is an oral inhibitor of the protein kinase Cbeta isozyme.

Fenretinide - analog of vitamin A
(4-HPR)

Indication: Lymphoma/CLL
 
fenretinide (fen-REH-tih-nide)

"Fenretinide may cause ceramide (a wax-like substance) to build up in tumor cells and kill them. It is a type of retinoid, which are substances related to vitamin A. "  Source | See also CLLtopics overview

GMX1777 (NAMPRT inhibitor)

Indication: Lymphoma/CLL
 
Small molecule pro-apoptotic agent... aimed at the key mechanisms of resistance to apoptosis, which play a central role in cancer cell survival.  Source  

Obatoclax mesylate (small molecule pan–Bcl-2 family antagonist (GX15-070)

Indication: Lymphoma/CLL/MCL

a small molecule pan-Bcl-2 antagonist with in vitro activity against chronic lymphocytic leukemia (CLL) cells.

NEW Clinical dose-finding activity and safety report:  bloodjournal.hematologylibrary.org

HA14-1 (inhibitor of Bcl-2)

Indication: Lymphomas/CLL
 
HA14-1, a small molecule Bcl-2 antagonist, induces apoptosis and modulates action of selected anticancer drugs in follicular lymphoma B cells.

YM155 (inhibitor of survivin)

Indication: Lymphomas 
 
A novel proapoptotic agent with potential antineoplastic activity. Survivin inhibitor YM155 selectively inhibits survivin expression in tumor cells, resulting in inhibition of survivin antiapoptotic activity (via the extrinsic or intrinsic apoptotic pathways) and tumor cell apoptosis.

www.cancer. gov

NEW Clinical Trial Report http://jco.ascopubs.org/content/26/32/5198.long

Immunotherapy
Activating the immune system to identify and inhibit cancer cells  
Also see Immunotherapy

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Description

See our report on
the NEJM report

Genetically Engineered Lymphocyte therapy http://1.usa.gov/rv1Bmn

 
1018 ISS - Toll-Like Receptor-9 (TLR-9) agonists (immune modulation)

Indication: Lymphoma, follicular
 
Toll-Like Receptor-9 (TLR-9) agonists have pleotropic effects on both the innate and adaptive immune systems. 

Background and early clinical results: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747261/

Actimune (interferon gamma-1b)

Indication: B-cell lymphoma
 
intra-tumoral injections of an adenoviral vector construct containing the human interferon gamma gene

ALERT: eHealthMe report on side effects

AD-Ifng  - Genetic: Adenovirus Interferon gamma (TG1042)

Indication: Lymphoma, cutaneous b- or t-cell
 
TG1042 is a third-generation, non-replicating human adenovirus vector containing a human IFN-gamma cDNA insert." Source
Data: http://www.biovalley.com/images_messages/image2/749.pdf 
 

CPG-7909 toll-like receptor-9 agonist
(PF-3512676, ProMune^®):

Indication: Lymphoma, cutaneous b- or t-cell

CpG oligodeoxynucleotides (ODNs) are TLR9 agonists that show promising results as vaccine adjuvants and in the treatment of cancers, infections, asthma and allergy. See expertopin.com 

NEW: VTX-2337 toll-like receptor 

Indication: Lymphoma, cutaneous b- or t-cell

"Toll-like receptors (TLRs) have emerged as attractive targets for anti-cancer immunotherapies. VTX-2337 is a novel, potent and selective small molecule (<500 MW) TLR8 agonist which activates myeloid dendritic cells, monocytes and NK cells to produce chemokines and Th1 polarizing cytokines, including TNFα, IL-12 and IFNγ. Such impacts induce innate and adaptive immune responses against tumor cells." See ASCO 2011 

Idiotype vaccines (all types)

Indication: Lymphoma expressing idiotype
 
The making of idiotype (autologous) vaccine starts with a biopsy (sometimes blood) to acquire fresh tissue. The idiotype protein (tumor-specific antigen) is isolated from the tumor. To make the vaccine more visible to the immune system (immunogenic), the Idiotype is bound with an adjuvant that is known to stimulate an immune response, such as KLH.

Idiotype protein vaccine, pulsed with dendritic cells

Indication: Lymphoma
 
Tumor-specific proteins expressed by B-cell lymphomas (idiotype [Id]) may serve as an effective antigen to induce active immunotherapy. We have previously described the vaccination of 4 patients with follicular lymphoma using dendritic cells (DCs) pulsed with tumor-derived Id protein  Source

Interleukin 2 (Aldesleukin) 

Indication: Lymphoma
 
"an interleukin, or hormone of the immune system that is instrumental in the body's natural response to microbial infection and in discriminating between foreign (nonself) and self. IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes, the cells that are responsible for immunity." Wikipedia

Interleukin 21 (IL-21)

Indication: Lymphoma

"IL-21 is a cytokine that could promote the anti-tumor responses of the innate and adaptive immune system.  Source

 ISF-35

Indications: CLL and lymphomas
 
Intra-nodal injection of adenovirus encoding recombinant CD40-ligand (Ad-ISF35) in patients with CLL.  ASCO 2009
 
Methods of Increasing Cancer Sensitivity to Chemotherapeutic Agents Using Chimeric ISF35 

Lenalidomide - immune modulator
(Revlimid (r) / CC-5013)

APPROVED for MDS and Myeloma

Possible indications: CLL / NHL / MDS
 
The analogues of thalidomide Source
 
Mechanisms PubMed 
Outcome ASCO | Medscape | PubMed
Safety ASCO | PubMed 

What is the right dose in CLL?
http://bloodjournal.hematologylibrary.org  

Lenalidomide (Revlimid) Oral Monotherapy Produces Durable Responses in Relapsed or Refractory Indolent NHL http://bit.ly/1SKZQH 

ALERT: eHealthMe real world reports on side effects

Aldesleukin (Proleukin)

Indication: Lymphoma
 
Recombinant interleukin-2 (IL-2)

Intercellular Cancer Pathways 
(Molecular targets)
Drugs that target cellular processes (transcriptional / epigenetic / enzymes) 
that cause malignant behavior (loss of cell growth and survival controls)

Signal Transduction Inhibitor Therapy for Lymphoma Lymphoma: http://bit.ly/eozc1S

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Description

APT 888 - targets PARP-1 /2

Indication: lymphoma, CLL
 
"a potent PARP inhibitor, enhances the antitumor activities by a variety of chemotherapeutic agents in vivo"
 

AR-12 - PDK-1 Inhibitor
Targeting the PI3K/Akt Pathway

Indication: Lymphomas

Phase I of AR-12, a PDK-1 Inhibitor Targeting the PI3K/Akt Pathway   http://bit.ly/13CT7p  

Sponsor: "AR-12 is potentially a first-in-class, orally available, PDK-1 (pyruvate dehydrogenase kinase isozyme 1) inhibitor that targets the PI3-K/Akt ocogenic pathway and also induces autophagy and the endoplasmic reticulum mediated apoptosis stress pathway."

BAY 43-9006 inhibits RAF kinase (Sorafenib/Nexavar)

Indication: Lymphomas
 
NBAY 43-9006 is a "targeted drug" specifically engineered to inhibit something called the RAF kinase within the cancer cells. RAF in turn is part of the RAS oncogene pathway. RAS is a gene which drives cell division and is over-expressed in many cancers. Source

BCX-1777 - PNP-inhibitor  (Forodesine)

Indication: Lymphoma, t-cell cutaneous
 
Recently a few new purine nucleoside analogues (PNA) have been synthesized and introduced into preclinical and clinical trials. The transition-state theory has led to the design of 9-deazanucleotide analogues that are purine nucleoside phosphorylase (PNP) inhibitors, termed immucillins. Among them the most promising results have been obtained with forodesine.

http://www.ncbi.nlm.nih.gov/pubmed/17897085

•  ASH: Forodesine HCl active single oral agent for advanced refractory CTCL abstracts2view.com 

Bruton's (Btk) tyrosine kinase inhibitor,  (PCI-32765)

Indication: b-cell Lymphomas and Leukemias

Bruton's tyrosine kinase is the gene that is disrupted in the human disease X-linked agammaglobulenemia (XLA). Patients with XLA are devoid of mature B-lymphocytes and immunoglobulins in the bloodstream, but are otherwise healthy. XLA thus provides strong clinical rationale for development of a novel therapeutic drug targeting Btk for safe inhibition of B-cell mediated diseases. In preclinical studies, PCI-32765 has the remarkable ability to selectively inhibit human B-cell activation without effecting T cells. Strong preclinical validation of Btk as a target in lymphoma was generated using PCI-32765 in a mouse model of B-cell receptor-driven lymphoma and in spontaneous B-cell lymphoma in companion canines.

Source: http://news.prnewswire.com/ 

More

CAL-101 - inhibitor of PI3k delta

Indication: Lymphomas / CLL
 
Phosphoinositide-3 kinase (PI3K) mediates critical intracellular signaling pathways that promote cell proliferation, growth, motility, metabolism and survival.

Interim Results From a Phase 1 Study of CAL-101, a Selective Oral Inhibitor of PI3K in Patients with Relapsed or Refractory Hematologic Malignancies Slides ASCO 2010 http://bit.ly/hqMLvL

N =106, (99 evaluable) relapsed/refractory, mixed histologies (CLL, indolent NHL, DLBC, MCL, AML, MM)

Ixabepilone - epothilone B analogs -  (BMS-247550)

Indication: Lymphomas
 
Epothilones are microtubule-stabilizing cytotoxic macrolides. "The epothilone B analogs are non-taxane tubulin stabilizing compounds that are active in taxane-resistant and -sensitive preclinical models."  Source

Report - phase I, dose-finding http://jco.ascopubs.org
Report with discussion of mechanisms annonc.oxfordjournals.org

Perifosine - Akt / P13K inhibitor,
(KRX-0401)

Indication: Lymphomas/CLL
 
KRX-0401 (perifosine) is a novel, potentially first-in-class, oral anti-cancer agent that inhibits the phosphoinositide 3-kinase (PI3K)/Akt pathway and several other key signal transduction pathways in both hematologic and solid tumor cancers.

CDK inhibitor  - SCH 727965 / dinaciclib

Indication: Lymphomas/MCL/CLL

"selectively inhibits cyclin dependent kinases CDK1, CDK2, CDK5, and CDK9; inhibition of CDK1 and CDK2 may result in cell cycle repression and tumor cell apoptosis"

Detailed background: Development of cell-cycle inhibitors for cancer therapy M.A. Dickson, MD* and G.K. Schwartz, MD*
http://bit.ly/cfIfjE
 

Temsirolimus (CCI-779) -
mTOR kinase inhibitor

Indication: Lymphomas/MCL/CLL

"Used as single agent achieved an overall response rate of 38% in relapsed MCL patients. Source 

Phase III study of patients with relapsed, refractory mantle cell ASCO 2007  

Temsirolimus Has Activity also in Non–Mantle Cell NHL
http://bit.ly/dn8Q6R 

Enzastaurin - inhibits signaling through the PKC-beta and PI3K/AKT pathways

Indication: Lymphomas

Orally administered protein kinase C-beta (PKCbeta) inhibitor Source

Also see NEWS: http://www.docguide.com/news/ 

Also see NEWS www.docguide.com/news

Everolimus - mTOR inhibitor (RAD001)

Indication: Lymphoma, MCL 
 
Everolimus Active in Relapsed Aggressive Non-Hodgkin’s Lymphoma  http://clinicaloptions.com  | Background 
 

	Target of rapamycin (mTOR) inhibitors in NHL
	Overall response rate: 32%
	Treatment well tolerated over extended duration
	Interim data support further investigation

Flavopiridol - inhibits CDK4-cyclin D1 complex (alvocidib)

Indication: Lymphomas, b-cell / CLL 
 
"The cell cycle regulatory protein cyclin D1, which is over-expressed in 95-100% of mantle cell lymphomas (MCL), is a potential therapeutic target." Source 

http://cat.inist.fr | jco.ascopubs.org |
pubmedcentral.nih.gov 

Oblimersen - RNA antisense, Bcl-2 inhibitor (Genasense)

Indication: Lymphoma / CLL
 
"The components of the apoptotic program are targets for anticancer therapy. Bcl-2 protein inhibits apoptosis." Source

GSK2126458 - targets PI3K

Indication: Lymphoma / CLL
 
PI3K-Akt pathway: its functions and alterations in human cancer. http://www.ncbi.nlm.nih.gov/pubmed/15505410? 

Fostamatinib Disodium (FosD) -  Syk kinase inhibitor

Indications: t and b-cell Lymphoma / CLL

"An orally available disodium salt of the Syk kinase inhibitor ..."  http://www.cancer.gov/ 

Report: Well-Tolerated and Has Significant Clinical Activity in DLBCL and SLL/CLL

http://ash.confex.com/ash/2008/webprogram/Paper5094.html 

KX2-391 - orally active Src kinase inhibitor

Indication: Lymphomas

An orally active Src kinase inhibitor with excellent
bioavailability.

MLN8237 - small molecule Aurora A kinase inhibitor

Indication: Lymphomas

a Novel Aurora A Kinase Inhibitor.

"The Aurora A kinase is required for cells to proceed through mitosis (cell division) and therefore, represents an attractive oncology therapeutic target."  http://www.reuters.com 

tamatinib fodium - syk kinase inhibitor (R788/R406)

Indication: Lymphoma

"R788/R406 is a novel syk kinase inhibitor that blocks the activation of mast cells, B-cells and macrophages by blocking IgG signaling.  Source

Sirolimus - mTOR inhibitor (rapamycin)

Indication: Lymphoma

The anti tumor potency of the mTOR inhibitor rapamycin (sirolimus) is the subject of intense investigations. Source

SB1518 - inhibitor of JAK2 kinase, and its JAK2V617F mutant

Indication: Lymphomas
 
Update: SB1518 Oral JAK-2 Inhibitor SB1518 active in Patients with Relapsed Lymphoma http://bit.ly/SB1518

SNSO32 - targets cell-cycle and transcriptional regulation 

Indication: Lymphomas, CLL, MCL
 
(formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. 

Daclizumab (Zenapax) - anti-Tac 

Indication: Lymphomas, t-cell, Hodgkin's
 
"Daclizumab (Zenapax) identifies the alpha subunit of the interleukin-2 (IL-2) receptor and blocks the interaction of this cytokine with its growth factor receptor. nature.com

Clinical trials:  Dasatinib AND NHL OR CLL http://bit.ly/a5HDEd

Histone Deacetylase (HDAC) Inhibitors

Epigenetic - non-genetic factors cause the organism's genes to behave
(or "express themselves") differently

A new class of lymphoma drugs that can induce tumor cells to die by silencing or restoring the expression of genes involved in the aberrant behavior of the malignant cells.

This cartoon shows how HDAC inhibitors may work:  ncbi.nlm.nih.gov/

(“DNA that is tightly wrapped around a deacetylated histone core relaxes” allowing “silenced” genes to function normally)

See also Histone deacetylase inhibitors as novel anticancer therapeutics http://bit.ly/cO5boB  
 
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Description

Azacytidine (Vidaza®)

Indications:  Lymphomas and MDS

One report on clinical safety report for Azacytidine:
http://clincancerres.aacrjournals.org/content/14/19/6296.full

Romidepsin - pan-HDAC inhibitor (Depsipeptide / FR901228/FK228)

Indications: Lymphomas / CLL /
t-cell lymphoma /CTCL (approved recently)
 
Phase 2 Data for Romidepsin Showing Durable Response in Refractory CTCL businesswire.com 

Romidepsin Induces Complete Response in Peripheral T-Cell Lymphoma http://bit.ly/fUANBl

Panobinostat - pan deacetylase inhibitor (LBH589)

Indication: Hodgkin Lymphoma, t-cell cutaneous

Oral administration. 

Response to the pan deacetylase inhibitor panobinostat (LBH589) in refractory Hodgkin Lymphoma. ncbi.nlm.nih.gov 

MS-275 - orally available inhibitor of HAC

Indication: CLL / Lymphomas

PCI-24781 - hydroxamic acid-based HDAC inhibitor

Indication: Lymphoma / CLL
 
"Currently 16 patients have been enrolled to date in a multicenter Phase I/II monotherapy trial in refractory lymphoma. From 10 patients evaluated to date, PCI-24781 has shown good activity (70% PR+SD) as a single agent, with one partial response in follicular NHL and verified stable diseases in SLL, CTCL, Hodgkin's disease and follicular lymphoma."  drugs.com    

PXD101 - hydroxamate HDAC inhibitor

Indication: Lymphoma, t-cell, MDS
 
A phase 1 trial of intravenous PXD101 treatment in patients with advanced solid tumors proved PXD101 to be clinically well tolerated at doses leading to prolonged pharmacodynamic effects such as acetylation of circulating white blood cells."

 http://meeting.ascopubs.org   

Valproic acid - HDAC inhibitor

Indication: Lymphoma, cutaneous t-cell
(APPROVED for other indication)

Valproic acid is a well-tolerated anticonvulsant that has been identified recently as a histone deacetylase inhibitor. http://bit.ly/7RnWwR

Valproic acid monotherapy leads to CR in a patient with refractory diffuse large B cell lymphoma.
http://www.ncbi.nlm.nih.gov/pubmed/17577787  (no abstract)

Vorinostat (Zolinza) - HDAC inhibitor

Indication: Lymphoma, cutaneous t-cell (APPROVED)

SAHA Histone deacetylase inhibitor. 

SAHA in patients with NHL  ASCO 2007

Report on Vorinostat for Relapsed or Refractory Indolent NHL and Mantle Cell Lymphoma http://bit.ly/dGBVLp 

Targeting the Proteasome
 
Proteasomes, similar to automobile exhaust systems, are complexes within the cell that degrade byproducts of cell activity.  Cancer cells, being metabolically active, depend on this process more than normal cells. 

Drugs that inhibit the proteasome "prevents degradation of the intracellular proteins, affecting signaling within cells,"  leading to cancer cell death or inhibition of growth. 

(See process illustrated: onsopcontent.ons.org )
 
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Bortezomib (Velcade / PS-341) - inhibits proteasome system

APPROVED FOR MCL

Indications: Lymphomas / CLL other cancers 

Related Abstracts:  proteasome inhibitors

NEW Carfilzomib - inhibits proteasome system

Indication: Lymphoma / CLL
 
An "irreversible tetrapeptide proteasome inhibitor derived from the natural product epoxomicin. Thus far, intensive dosing with carfilzomib is well-tolerated at proteasome inhibition levels of more than 80%."

Clinical: Five responses have been observed, and several subjects have achieved long lasting SD and/or symptomatic improvement. Source

Comment: It will be interesting to see if this agent proves to be as good or better than bortezomib in respect to both toxicity and efficacy.  Early clinical results are encouraging.

Salinosporamide (NPI-0052) - inhibits proteasome system

Indication: Lymphoma / CLL
 
An irreversible inhibitor (NPI-0052) on 20S chymotryptic proteasome activity and apoptosis in isolated CLL cells in vitro. Source

All such agents -
inhibit proteasome system

Related Abstracts:  proteasome inhibitors

Cytotoxics

Agents that trigger apoptosis (programmed cell death)
by damaging DNA - particularly in dividing cells.

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Bendamustine (Treanda, SDX-105)

Indication: Lymphoma / CLL APPROVED for CLL (March 2008)

Indication: Lymphoma, b-cell. Approved for CLL ... will likely be available off-label for other lymphomas.  
 
"a hybrid cytotoxic agent that is differentiated from conventional alkylating anti-cancer therapies in its apparent multi-functional mechanism of action" Source

Effective in relapsed or refractory aggressive NHL  cancerconsultants.com

Full Prescribing information: FDA as PDF file

BBR 2778 is a novel aza-anthracenedione that has activity in experimental tumors and shows reduced potential for cardiotoxicity in animal models. This cytotoxic agent has structural similarities with mitoxantrone as well as general similarities with anthracyclines (such as the tricyclic central quinoid chromophore). Source

 NEWS: Pixantrone Produces High Rates Of Complete Remission In Multiple Relapsed And Refractory Indolent And Aggressive Non-Hodgkin's Lymphoma medicalnewstoday.com 

Pralatrexate 
(Folotyn)

cyotoxic
inhibits DNA enzyme

Indication: Lymphomas

PDX is a novel, small molecule chemotherapeutic agent that inhibits dihydrofolate reductase, or DHFR, a folic acid (folate)-dependent enzyme involved in the building of nucleic acid, or DNA, and other processes. PDX was rationally designed for efficient transport into tumor cells via the reduced folate carrier, or RFC-1, and effective intracellular drug retention. 

The Company believes these biochemical features, together with preclinical and clinical data in a variety of tumors, suggest that PDX may have a favorable safety and efficacy profile relative to methotrexate and certain other DHFR inhibitors.  Source clfoundation.org 

Hot item for T-cell lymphoma: Pralatrexate, a novel class of antifol with high affinity for the reduced folate carrier-type 1, produces marked complete and durable remissions in a diversity of chemotherapy refractory cases of T-cell lymphoma. Br J Haematol. 2007 Nov;139(3):425-8. PMID: 17910632 

Nelarabine (506U78)

Indication: APPROVED  for treatment of adult and pediatric patients with T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma whose disease has not responded to, or has relapsed after treatment with, at least two chemotherapy regimens.
 
A nucleoside analog pro-drug of (see mechanism) 9-beta-D-arabinofuranosylguanine.  Source

Angiogenesis

Tumors may depend on blood supply to grow and survive.

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Indication: Lymphomas
 
Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF-A). Source

Other and Unknown Targets / Mechanisms

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Indication: Lymphomas, t-cell / GVHD
 
"Alefacept (well tolerated in treating psoriasis) reduced the number of CD4(+) and CD8(+) T cells, with selectivity for the memory subsets"   

Alefacept is well tolerated in patients with chronic plaque psoriasis.
J Cutan Med Surg. 2004 Dec;8 Suppl 2:14-9. Review.
PMID: 15668751
 

In Situ Tumor Ablation Creates an Antigen Source for the Generation of Antitumor Immunity  aacrjournals.org 

Early

or

to be added

AVI-4126 - inhibits MYC oncogene

Indication: Lymphomas
 
Novel anti-sense "The inactivation of MYC may be a specific and effective treatment for these tumors." Source

(none listed 
as of 07/08)

Affinitak - targets protein kinase C-alpha

Indication: lymphoma, not yet specified
 
"ISIS 3521 (Affinitak™, LY900003 / (ISIS3521)) is a phosphorothioate anti-sense oligonucleotide compound that selectively inhibits the production of protein kinase C-alpha."

(none listed 
as of 07/08)

Combining Targeted Therapies

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Epratuzumab (anti-cd22) AND Rituxan

Lenalidomide AND Rituxan

Veltuzumab (Anti-CD20) AND
Fractionated 90Y- Epratuzumab (Anti-CD22) Radioimmunotherapy

CAL-101 AND Bendamustine AND Rituximab

ACTIVE, BUT NOT RECRUITING
or COMPLETED or TERMINATED

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COMPLETED - no data

CS-1008

CS-1008 (humanized anti-DR5 antibody) targets 
TRAIL receptor

TeramMore (EM-1421)

selective inhibition of specificity protein 1 (Sp1)-regulated proteins Source

XK469

Indication: Lymphoma expressing CD2
 
2-[4-(7-chloro-2-quinoxalinyloxyphenoxy]-propionic acid (XK469; a new Topo IIß inhibitor) 

Azacitidine (MGCD0103)

Indication: Lymphomas
 
MGCD0103 is a rationally designed, oral, isotype-specific small molecule HDAC inhibitor which has been designed to be a molecular-targeted cancer therapy. MGCD0103 is currently in clinical trials in Canada and the United States. 
Source: www.methylgene.com

Completed, not recruiting

Elsamitrucin (SPP 28090)

Indication: Lymphomas: NHL, CLL
 
A heterocyclic antitumor antibiotic

Results: springerlink.com

Completed, not recruiting

MDX-010 (anti-CTLA-4)

Indication: Lymphomas

CTLA-4 is expressed on regulatory t-cells which may promote immune tolerance of malignant cells.