targeting proteins that may aid in tumor evasion of the immune system

[Guest guest]

An interesting (apparently low toxic) approach that might also revitalize

vaccine research if early signals of activity and safety are reproduced /

validated.

==

Phase I Safety Study of CT-011, a Humanized Antibody Interacting with PD-1,

in Patients with Advanced Hematologic Malignancies

CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune

response through interaction with PD-1, a protein belonging to the B7

receptor family present on lymphocytes. The objectives of this phase I study

were to assess the dose-limiting toxicities, to determine the maximum

tolerated dose, and to study the pharmacokinetics of CT-011 administered

once to patients with advanced hematologic malignancies.

The B7 family of co-signaling molecules is expressed on the surface of T

lymphocytes and is crucial for their optimal activation, as well as for the

prevention of immunologic tolerance (1

<http://clincancerres.aacrjournals.org/content/14/10/3044.full#ref-1> ).

These co-signaling molecules not only provide critical positive signals that

stimulate T-cell growth, up-regulate cytokine production, and promote T-cell

differentiation, but also contribute key negative signals that limit,

terminate, and/or attenuate T-cell responses (2

<http://clincancerres.aacrjournals.org/content/14/10/3044.full#ref-2> -5

<http://clincancerres.aacrjournals.org/content/14/10/3044.full#ref-5> ).

Anticancer immunotherapy based on antibodies directed against the B7 family

of receptors, particularly the B7 homologue 1 (B7-H1)-programmed death 1

(PD1) system, suggests a promising novel approach for promoting immune

responses against cancer as well as breaking up tumor resistance and

dormancy.

..

Although this first in-human phase I study was not designed to address

questions of efficacy, the following evaluations were done during the study:

clinical response, ECOG performance status, and survival. These findings are

presented for exploratory purposes only. All patients who participated in

the study, with the exclusion of the two patients who withdrew, were

evaluated for clinical responses and survival.

..

There was one complete remission in patient 015 that received the fourth

dose level of 3.0 mg/kg. This patient was diagnosed with stage III

follicular lymphoma involving nodes below and above the diaphragm. The

patient did not receive any prior treatment for her disease. In a computed

tomography scan done during a periodic check 10 months after CT-011

treatment, complete elimination of tumor masses was observed. Interestingly,

the patient did not receive any further treatment during the period that

lapsed between CT-011 treatment and the 10-month check. The patient has

shown a sustained remission 68 weeks following CT-011 treatment.

One minimal response was observed in an AML patient receiving CT-011 at 0.2

and 3 mg/kg. The patient progressed 61 weeks after receiving CT-011. Four

patients have shown stable disease: One with Hodgkin's lymphoma receiving

CT-011 at 0.6 mg/kg had a stable disease for 35 weeks. Two patients with

chronic lymphocytic leukemia receiving the antibody at 0.6 and at 1.5 mg/kg

were stable for 36 and >78 weeks, respectively. A multiple myeloma patient

receiving CT-011 at 6.0 mg/kg showed stable disease for >60 weeks.

Full text: http://bit.ly/a3lHUc

Clinical Trials: http://bit.ly/1Bj7r1 (one recruiting at MDACC)

All the best,

~ Karl

Patients Against Lymphoma

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