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Research at Mass General
Mark Cobbold, MRCP, PhDMember of the Faculty of Medicine, Harvard Medical School
The Cobbold laboratory focuses on understanding how the healthy human immune response is able to recognize and target cancerous cells, and when it fails, how it could be strengthened to recognize this endogenous threat. Our immune system faces a challenge in targeting cancerous cells as they are not “foreign” yet subtle changes in the cellular proteins exist that nevertheless allow our immune cells (T-cells) to detect them. Cancer cells modify internal proteins in different ways to healthy cells, a process fundamental to a cell becoming cancerous. These abnormal modifications can be recognized by T-cells and we believe play a role in protecting us against cancer.
In patients with cancer, this immunity is often lost and therefore new approaches may be needed. We are developing therapeutics that mobilize existing potent immune responses to instead tackle cancer. These immune-based therapies make cancerous cells appear virally infected in the hope that our own anti-viral immunity could step in to fill the void.
Mark Cobbold, MRCP, PhDPrincipal Investigator
Recently, new therapies such as checkpoint blockade therapies have revealed potent underlying anti-tumor immunity in patients with many types of cancer. The nature of the tumor antigens targeted by endogenous immunity is still being characterized, but “altered-self” antigens (neoantigens) are thought to play a dominant role. Neoantigens can be generated through genetic mutations that lead to changes in protein sequence (so called “mutational neoantigens”), but these types of antigens are typically unique to each tumor and thus any approach targeting these would need to be in a form of a personalized therapeutic.
We have identified posttranslational modifications (phosphorylation, glycosylation and methylation) as additional mechanisms whereby proteins can be abnormally modified allowing immune recognition. Thus, aberrant signaling renders phosphate, methyl-, or N-GlcNAc protein adducts as pathophysiological haptens. These antigens are abundantly displayed on the surface of cancer cells bound to MHC class-I molecules and we have identified over 1,000 phosphorylated peptides found on primary tumors. In contrast to classical neoantigens, the surface-display of posttranslationally modified neoantigens isshared between many tumor types potentially affording a broader targeting approach.
This class of tumor antigens exhibits interesting MHC binding with, for example, increased affinity for MHC molecules over non-phosphorylated counterparts. Moreover, structural studies reveal an MHC surface binding pocket facilitating the presentation of the phosphate groups to T-cells (Nature Immunology 2008). This recognition pathway may have evolved to allow T-cells to scrutinize underlying cellular signal transduction pathways directly linking adaptive immunity with protection against fundamental oncogenic processes.
We have shown the existence of memory-like T-cells in healthy individuals that recognizes leukemia-associated phosphopeptide antigens, yet this immunity is lost in patients with leukemia (Science Translational Medicine 2013). Immunotherapies, such as stem cell transplantation where healthy donor immunity is transferred to patients, restore this immunity providing some evidence for its potential utility. Thus posttranslationally modified antigens represent a new class of neoantigens, but their importance in cancer remains to be determined.
T-cell Activating Therapeutics
When detected in the blood, immunity against cancer is known to be weak, exhibiting low frequencies and of compromised function. This contrasts starkly against immunity toward persistent viruses such as human cytomegalovirus (CMV) or Epstein-Barr virus (EBV) which typically occupy exceptionally high frequencies in both blood and tissues. Moreover, it is known that CMV immunity increases with age and is preserved in patients with cancer, thus making it ideal to harness against tumors.
Most recently, we have advanced the notion of altered-self and developed a technology that is able to manipulate the types of antigens present on the surface of tumor cells. We utilized dominant CMV antigens (we term “über-antigens”) to develop peptide payloads that could be conjugated to tumor-targeting antibodies. These complexes allow surface release of the über-antigens with subsequent passive loading into empty MHC class-I molecules by exploiting proteases expressed by cancer and engineering antigens that can be processed by these proteases (Millar et al manuscript in preparation). Thus this approach circumvents the requirement in the host of potent anti-cancer immunity which is lacking.
Wong GK, Millar D, Penny S, Heather JM, Mistry P, Buettner N, Bryon J, Huissoon AP & Cobbold M. Accelerated Loss of TCR Repertoire Diversity in Common Variable Immunodeficiency. J. Immunol. 2016 Sep 1;197(5):1642-9. PMID: 27481850.
Cobbold M*, De La Peña H, Norris A, Polefrone JM, Qian J, English AM, Cummings KL, Penny S, Turner JE, Cottine J, Abelin JG, Malaker SA, Zarling AL, Huang HW,Goodyear O, Freeman SD, Shabanowitz J, Pratt G, Craddock C, Williams ME, Hunt DF, Engelhard VH. MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia. Sci Transl Med. 2013 Sep 18;5(203):203ra125. * Corresponding Author
Mohammed F*, Cobbold M*, Zarling AL, Salim M, Barrett-Wilt GA, Shabanowitz J,Hunt DF, Engelhard VH, Willcox BE. Phosphorylation-dependent interaction between antigenic peptides and MHC class I: a molecular basis for the presentation of transformed self. Nat Immunol. 2008 Nov;9(11):1236-43. doi: 10.1038/ni.1660. Epub 2008 Oct 5. PubMed PMID: 18836451. * Joint first author
Cobbold M, Khan N, Pourgheysari B, Tauro S, McDonald D, Osman H, Assenmacher M, Billingham L, Steward C, Crawley C, Olavarria E, Goldman J, Chakraverty R, Mahendra P, Craddock C, Moss PA. Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers. J Exp Med. 2005 Aug 1;202(3):379-86. PubMed PMID: 16061727.
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