From Terry's Techniclone Terrace Nov. 17 1998 by golfdad97
Disclaimer should read as same as given for posts regarding
Rituxan. This information is meant to be solely for a basis of
informative discussion without regard to endorsement or claim for
efficacy (or lack thereof) of any product.
Oncolym, interestingly, is the marketed trade name for the
radiolabeled Lym-1 antibody when it is ready for infusion...piece
of trivia...in contrast to Lym-1 which is the antibody (mouse
class IgG2a, originally described by Epstein in 1987 concerning
his studies with a monoclonal antibody against an antigen defined
on the membrane of a cultured Burkitt lymphoma cell line. This
antigen was found to be a mutated form of a Class II recognition
antigen (in human systems, called HLA, for Human Leukocyte
Antigen)...and specifically, a recognition antigen found on
B-lymphocytes (and other cell types) of a subcategory called
HLA-DR. These molecules are involved in cell to cell
communication and exchange of molecular information regarding the
structure of foreign antigens; hence we make immune responses
using these recognition molecules. Now, in this lymphoma, this
molecule was mutated and Epstein was able to isolate a mouse
lymphocyte that makes monoclonal antibodies to it. You can scale
up and make a ton of it if necessary and try to treat lymphoma
patients if they carried the same molecule on the surface of
their B-cell lymphomas (and the rest is history). The best I
could track in the literature and I assume there are people
familiar with the TCLN message board who go back more than a
decade into the beginning of TCLN and may be able to offer more
insight into any early studies regarding the use of Lym-1 in
therapy of lymphoma, but I could only really track the scientific
literature.
Most of the published work on Lym-1 comes from the prolific
laboratory of the academic group of Sally and Gerald DeNardo at
the University of California at Davis. However, there are two
major differences that I observed in my reading of the literature
on the clinical use of Lym-1 and the literature associated with
Bexxar and Rituxan...namely, (1) the lack of apparent funding for
the expanded clinical trials needed for Lym-1 as determined by
the limited number of trials being conducted and (2) the
marvelous scientific methodologies used by the DeNardos in
attempts to clearly define the parameters of successful therapy
of lymphoma using radiolabeled antibodies. They have set the
standard for defining conditions of antibody localization,
dosimetry and predictive parameters that help to define exactly
who and under what conditions patients will respond to this form
of therapy. Will touch on this matter later, just for personal
interest. Although published perhaps in only abstract form years
ago, some initial therapy was attempted with the
"naked" Lym-1 antibody in lymphoma patients, which
would be the natural thing to do, since the antibody is of a
subtype (IgG2a) that could cause killing of the lymphoma cells
under favorable circumstances after binding...but this was not
observed. Interestingly, one of the first manuscripts was a case
study involving a patient with Ricter's syndrome, a somewhat
bizarre form of chronic lymphocytic leukemia and the patient was
nearly moribund with rapidly growing tumor. The patient was
successfully treated with a series of infusions with I131-Lym-1
with rapid shrinkage of the tumor sites and the patient was
described to be followed over the next 10 months (an average
survival for this syndrome was 4 months)...but I have not located
(nor searched very hard) a follow-up for this particular patient
since the study was an isolated incident published over a decade
ago. But it was worthy of historical note, and the initial
enthusiasm must have been exciting for the medical staff as well
as the family of this patient.
Pilot studies in Phase I were taking place before 1987 since one
of the first studies was published in 1988 describing treatment
of 10 patients with progressive, refractory B-cell malignancies
with radiolabeled Lym-1 (everything I write about here involves
the use of radiolabeled Lym-1). I will tend to skip through these
early studies (1988-1990) rather quickly since the follow-up
described in later papers are repetitive and the Phase I studies
were examining distribution of antibody, relative uptake at site
of tumor compared to normal tissues, etc. Early therapy consisted
of fractionated, relatively low doses (25-60 mCi) in intermediate
and high-grade patients, almost all with stage III and IV
disease, hence the toughest populations of lymphoma patients were
being treated...late stage disease, refractory to further
chemotherapy and progressive. Of an initial 18 patients, 10
responded (56%, complete or partial) by parameters described in
my earlier posts about the Rituxan and Bexxar therapies. Toxicity
with these low-doses was modest. However, a brief study published
in 1994 described the use of Lym-1 in 5 refractory CLL patients
and the use of high-end fractionated doses (up to 65 mCi at 2-6
week intervals) were leading to thrombocytopenia and the group
realized that strategies were needed to support this cytopenia
before high-dose radiotherapy would be a commonplace modality.
Several studies up to the present time from this first definitive
study of Lym-1 therapy have focused upon a reevaluation of data
already obtained and available while doing Phase I/II studies,
such as determining that there is no real reason to exclude
patients with splenomegaly (enlarged spleen, usually with tumor
burden) from therapy using Lym-1. A paper describing this
evaluation of a small subset of patients with splenomegaly was
given at the 6th Monoclonal Antibody Conference and also
published in Cancer. At the Eleventh International Conference for
Use of Monoclonal Antibodies in Cancer, in February of this year,
DeNardo presented a paper in the milestones of Lym-1 development,
describing in detail their analysis of importance of LDH/KS in
determining the response to this therapy (and probably similar
therapies under these conditions). In addition, at this meeting,
Jamie Oliver described the Phase I/II studies using multidose
therapy with Lym-1 in patients with intermediate or high-grade
lymphoma. This was co-authored by the DeNardos and carried the
byline of Techniclone Corp and USC-Davis. 33 patients with
recurrent or refractory intermediate/high grade disease. Doses
ranging from 2-200 mCi. Overall, 52% of the patients responded to
multidose therapy (CR or PR) with a mean durability of 13 months
and those receiving the higher doses had a higher rate of
response. Thrombocytopenia is dose-limiting (at about 160-200
mCi). An early report from the multicenter Phase II?III (?) study
was also given at this meeting, representing physicians from M.D.
Anderson Cancer Center, Cornell Univ., George Washington Med
Center, Iowa City VA, and Univ of Miami. Patients enrolled
received at least 1 prior chemotherapy and were eligible for up
to 4 doses at 160 mCi. 15 patients enrolled, and 9 received at
least one therapeutic dose...3 patients with response (1CR and
2PR) and clearly this study is too early to talk about or
successfully evaluate...this was earlier this year.
. This same story was repeated by both sets of authors at ASCO in
the spring. For those interested in detailed analysis, the
DeNardos published a detailed paper about a year ago in Clinical
Cancer Research outlining the analysis of predictive parameters
in patients upon which they had a very lot of clinical and
laboratory data. Suffice it to say that the development of
antimouse antibodies turns out to be a good prognostic factor for
ultimate survival time after therapy...i.e., those patients who
develop HAMA actually do better...representing some facet of the
immune response of these patients not readily apparent in its tie
to lymphoma. Two additional items. One, I posted a summary of the
recent paper published in Oct describing the value of high-dose,
fractionated radiotherapy with Lym-1 and I hesitate to repeat
that post here.... (See Post # 181 and 182 to Investor CG).
Finally, much of the summary of the therapy involving 88 patients
and a description of Phase III studies are given from a
description of prior news releases and can be found at:
http://www.wizard.com/NHL/research/Oncolym.htm