Anti-Cancer Responses in Metastatic Melanoma related to CTLA i believe

[bimazek]

this is an old press release for one or two years ago... put i believe that mdx-10 is a anti-CTLA monoclonal antibody that they were testing on cancer... what is interesting is the
balance between autoimmunity events and distruction of tumors ...CTLA is related to pd-1

strong simulated immune system                       weak exahausted pd-1 low immune system (like cd4 low low)
tumors disappear but there is                            tumors growing and immune system not taking care of them
autoimmune side effects                                   no   autoimmune effects

so that is a balance

http://www.medarex.com/cgi-local/item.pl/20030625-555576

Anti-Cancer Responses in Metastatic Melanoma Patients Linked to Immune Activation by MDX-010 Published in the `Proceedings of the National Academy of Sciences' (PNAS)

       Complete Responses Observed in On-Going Phase II Clinical Trial

  PRINCETON, N.J., June 25 /PRNewswire-FirstCall/ --
Medarex, Inc. (Nasdaq: MEDX) today announced the publication of positive
results from the initial cohort of 14 patients in an open-label MDX-010 Phase
II melanoma study in the Online Early Edition of the "Proceedings of the
National Academy of Sciences" (www.pnas.org) for the week of June 23, 2003.
In the study, an objective response rate of 21%, which included two complete
tumor responses, was observed in the initial cohort of 14 patients with
metastatic melanoma.  The trial was conducted by Steven A. Rosenberg, M.D.,
Ph.D., Chief of Surgery at the National Cancer Institute (NCI), and was the
first human study designed to assess the potential anti-tumor activity of MDX-
010, a fully human antibody that blocks CTLA-4, after repeated dosing in
combination with a peptide vaccine based on gp100 melanoma-associated
antigens.  Previous studies of this vaccine given alone without the antibody
in the treatment of metastatic melanoma demonstrated an objective response
rate of approximately 2%.

    The data also indicates that MDX-010 may be able to induce a reversible
state of autoimmunity, with an apparent correlation between the development of
drug-related autoimmunity and durable clinical responses.  Six patients
reported drug-related autoimmune adverse events (dermatitis, colitis,
hepatitis and hypophysitis), all of whom responded to medical therapy. Of the
patients who experienced these Autoimmune Breakthrough Events (ABEs), 50% also
experienced anti-tumor response. No patient experienced an anti-tumor response
without experiencing some ABE. The observations suggest that these drug-
related adverse events, or Autoimmune Breakthrough Events, may be associated
with the induction of anti-cancer immune responses.

    In the initial cohort of 14 patients with metastatic disease, all had
undergone surgical therapy for the primary lesion and received a regimen of
3.0 mg/kg of MDX-010 once every three weeks in combination with two peptides
from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-
288(288V).  Of these, two patients achieved complete responses, per the RECIST
(Response Evaluation Criteria in Solid Tumors) definition.  One of these two
patients experienced complete resolution of a 0.5 cm brain lesion, two
subcutaneous nodules and 31 lung metastases.  The second of these two patients
experienced complete resolution of an abdominal subcutaneous nodule and a
solitary lung lesion.  Prior to treatment with the MDX-010 antibody and gp100
peptide vaccine, both patients had received chemotherapy and undergone
surgical therapy, and one patient had also received previous immunotherapy.  A
third patient who had received previous immunotherapy achieved a partial
response with tumor shrinkage of a solitary lung lesion, lasting over 10
months after two treatment cycles.  Mixed responses were observed in two
additional patients.
(thanks jp after i posted i realized it was ctla)

QUESTION

WHAT ARE THE KEYS THAT FIT IN THESE RECEPTORS PD-1 AND CTLA AND IS THERE ANY NUTRIENTS THAT ARE INVOLVED IN THIER FUNCTION

I HAVE theory on several...

[JPinLA]

CTLA-4 is a recpetor much like PD-1.  Both are expressed on T-cells primarily activated T-cells (PD-1 on B cells as well).  They both are involved with regulation of T-cell activation/proliferation. Receptors like CTLA-4 and PD-1 transduce signals that are inhibitory to lymphocyte activation (see reference). The balance between "positive" and "negative" signaling is thought to enable effective immune responses while maintaining immunological tolerance and preventing autoimmunity (see reference).

MDX-10 targets CTLA-4 and inhibition of CTLA-4 produces a similar effect as inhibition of PD-1, impeding tolerance or exhaustion and maintaining activation.  They are structurally different, functionally similar and some of their signalling does overlap but it is not redundant. In the end, they both work to deactivate immune cells.

My point here is that PD-1 and CTLA-4 are two different receptors that serve very similar functions.  MDX-10 targets CTLA-4 not PD-1 but serves a similar purpose.

As a side note, I have worked with Medarex for years in producing full human monoclonal antibody therapetics where I work.  Very good technology.

JP




Parry et al. (2005) CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct MechanismsMolecular and Cellular Biology, November 2005, p. 9543-9553, Vol. 25, No. 21.

http://mcb.asm.org/cgi/content/full/25/21/9543.