2012 News

Dec 2012
Marasco appointed full professor

Dr. Marasco was promoted to full professor of medicine at Harvard Medical School

Read the story in Inside the Institute 


Dec 18, 2012
In the Media: CTCL project Highlight

DFCI News: A two-fisted blow against a deadly cancer   pdf


 Oct 25, 2012
The Marasco Lab has joined forces with the Harvard Stem Cell Institute (HSCI) to open two new Centers:

Center for Human Antibody Therapeutics (CHAT)

Humanized Neonatal Mouse Center (HNMC)


Sept 4, 2012
New Publication- Anti-CCR4 minibody for treatment of Cutaneous T Cell Lymphoma
August 6, 2012
New Publication- An Anti-CCR4 antibody that blocks Treg and kills Cutaneous T Cell Lymphoma (CTCL) cells

Cutaneous T cell lymphoma (CTCL) makes up about 5% of all non-Hodgkin lymphomas.  In CTCL patients, malignant T-cells from their own immune system migrate to the skin where they cause typical cutaneous lesions. Recent studies show that chemokine receptor CCR4 is highly expressed on CTCL cells and associated with their skin-homing capacity. CCR4 is also expressed on T regulatory cells (Tregs) that can be recruited to the tumor microenvironment due to secretion of CCR4 ligands (chemokine CCL17 and CCL22) by tumor cells. Normally, Tregs act to dampen the immune system and when they are recruited to the site of a tumor, they act to inhibit the host’s anti-tumor activity. Thus, the high expression of CCR4 found on both Treg and CTCL suggests that CCR4 may be a potentially ideal target for antibody-based immunotherapy against CTCL.

In a study performed by Chang and colleagues of the Marasco lab, mAb1567, a monoclonal antibody (mAb) that recognizes CCR4, was characterized and humanized from a mouse anti-CCR4 mAb and then further characterized. Through several in vitro studies the antibody was shown to exhibit potent anti-tumor effects in a CTCL mouse model by inducing complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). In addition, this humanized antibody inhibited Treg migration induced by the CCR4 ligand CCL22 and abrogated Treg suppression on T effector cells. In in vivo studies, the CTCL xenografted tumors were significantly reduced in size in anti-CCR4 mAbs treated groups. Lastly, an affinity maturation campaign resulted in a stronger binding antibody mAb2-3 against CCR4+ tumor cells that showed greater anti-tumor killing properties.

In a second publication by Han T et al., the effectiveness of humanized mAb1567 was evaluated in vivo for curative treatment of CTCL using a recombinant adeno-associated viral (AAV) vector-mediated minibody gene transfer into SCID-BEIGE mice.  The single direct intravenous (i.v.) injection indicated endogenous synthesis and durable expression of therapeutic antibody levels for months.  The results in this paper demonstrated in vivo evidence on the ADCC-mediated anti-tumor activities and the potency of mAb 1567 as a potential novel therapy for CTCL. The data further demonstrated the utility of the AAV-minibody gene delivery platform to rapidly evaluate novel anti-tumor mAbs, which may lead to a decrease in the time required for determining efficacy in pre-clinical studies.

The development of more effective cancer immunotherapy with better discrimination between tumor and normal cells is the most important goal of current anticancer research.  Monoclonal Antibodies (mAb) have been proven as viable cancer treatment options in the past 17 years with 13 FDA approved mAbs in clinic. Current therapies for CTCL do not prevent new lesions from emerging and long-term remission is rare, highlighting the need for more effective therapies for CTCL patients. The team hopes that mAb2-3 could become a more effective immunotherapeutic agent against CTCL, and because of its profound effects on Tregs, could also be used against other solid tumors that secrete the CCR4 ligands CCL15/CCL22 and attract immuosuppressing Tregs to the tumor site.  

Humanization of an anti-CCR4 antibody that kills Cutaneous T Cell Lymphoma cells and abrogates suppression by T regulatory cells.  Chang DK, Sui J, Geng S, Muvaffak A, Bai M, Fuhlbrigge RC, Lo AS, Yammanuru A, Hubbard L, Sheehan J, Campbell JJ, Zhu Q, Kupper TS and Marasco WA  Mol Cancer Ther.  2012 Aug 6.  PMID:22869555

Human anti-CCR4 minibody Gene Transfer for the Treatment of Cutaneous T Cell Lymphoma.  Han T, Abdel-Motal UM, Chang DK, Sui J, Muvaffak A, Campbell JJ, Zhu Q, Kupper TS and Marasco WA  PLoS OneSep 4 2012 | PMID:22973452 | PMCID:PMC3433438

 


 June 26, 2012
NEW PUBLICATION
- Anti-HIV Tat intrabody promotes survival of CD4+ cells In Vivo

In Vivo Selection of CD4+ T Cells Transduced with a Gamma-Retroviral Vector Expressing a Single-Chain Intrabody Targeting HIV-1 Tat.  Braun SE, Taube R, Zhu Q, Wong FE, Murakami A, Kamau E, Dwyer M, Qiu G, Daigle J, Carville A, Johnson RP and Marasco WA.  Hum Gene Ther. 2012 Jun 26.  PMID:22734618


 June 19, 2012
Dr. Marasco to speak at the NIH flu talks Bethesda, MD
The NIH is holding a two day series of talks to evaluate improving the influenza vaccines.  Dr. Marasco's talk is titled "Immunologic Challenges to the Development of a Universal Influenza Vaccine".


May 17, 2012
New Publication - Human antibody gene repertoire analysis in hNSG mice.

Human B-cell ontogeny in humanized NOD/SCID gcnull mice generates a diverse yet auto/poly- and HIV-1 reactive antibody repertoire.  Chang H, Biswas S, Tallarico AS, Sarkis PTN, Geng S, Panditrao MM, Zhu Q and Marasco WA.  Genes and Immunity. 13, 399-410 (July/August 2012) | doi:10.1038/gene.2012.16.  PMID:22592523

We performed an analysis of single-sorted human B cells from humanized NOD/SCID gc-/- (hNSG) mice at both genetic and functional levels. B cells from different stages of development, from early immature in the bone marrow to naïve mature in the periphery were sorted as single cells, the antibody genes cloned and expressed as single chain antibody fragments (scFvFcs). Sequence analysis of the antibody genes suggested an impairment in the checkpoint control mechanisms based on longer HCDR3 regions with high levels of positive charges found in the peripheral naïve mature B cells, a characteristic of auto/polyreactive antibodies. This observation was functionally confirmed by performing autoantigen binding analysis with the purified scFvFcs.  In addition, many of these poly/auto reactive antibodies demonstrated high affinity binding to HIV envelope protein.  These data suggest that the hNSG model (and BLT/GTL models) can be used to study the ontogeny of anti-HIV antibodies at the molecular level and may provide a unique model in HIV vaccine research.

  *  Publication highlighted in Cord Blood News 4.19, May 17, 2012


May 7, 2012
Affiliated Faculty Member of HSCI
Dr. Marasco has been named an Affiliated Faculty Member of the Harvard Stem Cell Institute (HSCI).  HSCI mission is "A scientific collaborative established to fulfill the promise of stem cell biology".  Dr. Marasco's work in developing unique mouse models for the study of human stem cell differentiation and of tissue regeneration is a complimentary addition to the research programs HSCI has established.


May 18, 2012 - 7th Annual HSCI Malkin Retreat, Harvard University, Northwest Lab Building, Lower Level, 52 Oxford St. Cambridge, MA

The Marasco Lab is presenting two posters at the Poster Session from 4-6PM.  Poster Titles are:
- Center for Human Antibody Therapies (CHAT)  Zhu Q, Marasco WA

- Establishing NeoNatal Mouse Models for the Evaluation of Human Stem Cell Biology and Their Potential in Regenerative Medicine  Sun J, Biswas S, Moniz R, Wang Y, Panditrao M, Zhu Q, Marasco WA


May 1, 2012
Dr. Marasco to speak at the PEGS conference, Boston, MA
The 8th Annual PEGS conference is being held at the Park Plaza Hotel & Towers, Boston, MA on April 30-May 4, 2012.  Dr. Marasco's  talk is titled " Human Anti-CCR4 mAb Immunotherapy for the Treatment of Cutaneous T-cell Lymphoma" on May 1, 2012 at 11:45.


 March 27, 2012

Dr. Marasco speaking at the Gordon Research Conference: Antibody Biology & Engineering, Galveston, TX
The GRC is from March 25-30.  Dr. Marasco will be speaking on Tuesday, March 27th.  The title of his talk is: "Challenges to a universal influenza vaccine".


 February  3, 2012
Launch of Humanized Mouse website - www.humouse.org
The Marasco Lab is happy to announce the launch of the Humanized Mouse website.  Since 2007, the Marasco Lab has successfully developed, characterized and optimized humanized mouse models. We are now opening up our expertise in the field to the larger research community.  Please read more about what we have to offer and how we can help take your research to the next level.


 January 13, 2012

Accomplished Structural Biologist joins the Marasco Lab

The Marasco Lab is pleased to announce the addition of Zhen Zhang to the lab.  Dr. Zhang is a protein biochemist and structural biologist with 12 years experience in protein engineering, expression, purification and characterization.  His expertise in protein crystallography will be used to further our work in the field of novel vaccine development to elicit broad-spectrum neutralizing antibodies against influenza viruses.