Cancer Alpha Therapy: Trials and Tribulations...Next trial: C595 for MUC1 •Our preclinical data...
Transcript of Cancer Alpha Therapy: Trials and Tribulations...Next trial: C595 for MUC1 •Our preclinical data...
Cancer Alpha Therapy:
Trials and Tribulations
Prof Barry J Allen PhD DSc
Director
Centre for Experimental Radiation
Oncology
St George Cancer Care Centre
How to introduce a new cancer therapy
• Define the problem
• New idea to address the problem
• Preclinical studies in vitro and in nude mice to confirm
the idea
• Translational studies
• Phase 1 clinical trial for dose tolerance
• Phase 2 trial for efficacy at maximum tolerance dose
• $$$$$ from industry for phase 3 trial for comparison
with standard therapy
• Clinical application in cancer centres
Status of cancer therapies
• Surgery is always the first option if possible.
• XBRT* continues to improve with intensity
modulated and conformal targeting with reduced
exposure to normal tissue. [*External Beam Radiotherapy]
• Brachytherapy for prostate is excellent.
• Local control of most cancers is very good; H&N
not so good; GBM very poor.
But patients still die from systemic disease.
Systemic problems
• Few therapies to stop the development of
advanced metastatic cancer from
micrometastases after local treatment of
primary.
• This is the achilles heel of cancer
management.
• Control of micrometastases means
improved prognosis .
Idea!!! Targeted Alpha Therapy
• Bi-213 radioisotope emits alpha radiation.
• Alpha radiation (8.4 MeV) is short range (80
µm) with high Linear Energy Transfer (LET)
and is highly toxic to targeted cells.
• Bi-213 labeled monoclonal antibody or protein
targets antigens expressed by cancer cells.
• Cancer cells and tumour blood vessel cells
killed, tumour regresses.
Why alphas?
Properties alphas betas toxins
Range ( m) 20-80 400-4000 zero*
Lifetime hours days weeks
Energy loss ~100 ~0.3 -
(keV/ m)
* Bystander effect?
Production of alpha emitting
radioisotopes
Actinium-225 : Bismuth-213 Generator
Ac-225 Isotope separation from Th-229,
imported into Australia
Ac-225 (10 d)-> Bi-213 (46 min)
ELEMENTS OF TAT
Radioisotope: Bi-213 (46 min) from Ac-225 (10 d)
Chelators: cDTPA; DTPA-CHX-A”
Targeting: 9.2.27 melanoma, GBM
WM-53 leukaemia
c30.6 colorectal
herceptin breast, ovarian
J591 prostate
C595 bladder, prostate, pancreatic
PAI2 breast, prostate, ovarian
Alpha conjugate: Bi213-chelator-MAb
What have we done?
• In vitro experiments
• In vivo studies
• Intralesional melanoma trial
• Systemic melanoma trial
• Biological dosimetry
Do
0 10 20 300.01
0.10
1.00
10.00
Do
Bi-213
Tb-152
Activity ( Ci)
Log
cel
l su
rviv
al
IN VITRO - MELANOMA
CONCLUSIONS - IN VITRO
1 Stable alpha-conjugates can be formed with mabs
and PAI-2.
2 Alpha-conjugates are highly selective of targeted
cancer cells.
3 In vitro cytotoxicity of alpha-conjugates:
>> beta conjugates,
>> non-specific alpha-conjugates and
>> free alpha isotope.
4 Lethal pathway is by apoptosis.
0 10 20 30 40 500
25
50
75Control
Mouse 2
Mouse 3
Mouse 4
Mouse 5
Post-inoculation period (d)
Tu
mo
ur
size
(m
m2)
In Vivo Melanoma: systemic2mCi/kg at 2 d post-inoculation of cancer cells
micrometastasis model
Intralesional TAT
CONCLUSIONS - IN VIVO
1 Activity tolerances: 8 mCi/kg for intra-peritoneal
injection.
2 Local TAT: complete inhibition of tumourigenesis
for all cancers.
3 Intralesional TAT: 300 Ci gives complete
regression of melanomas.
4 Systemic single dose TAT: all tumours experience
growth delay.
Intralesional TAT phase 1 clinical
trial - 2001
• Starting dose: 150 Ci for 3 patients, monitor
subjects at 2 and 4 weeks; HAMA assay.
• Increase by 300 Ci steps up to 1350 Ci for 15
patients.
• Measure pharmacokinetics with NaI detector over
injection site, kidneys, bladder.
• Derive clearance times in tumour and organs.
• Calculate organ exposures, dose detriment, cancer
risk.
Metastatic Melanoma
Tumour retention of alpha-RIC - Group IV (250uCi)
0.01
0.1
1
0 20 40 60 80 100 120
Time after injection (min)
Fra
cti
on
of
ad
min
iste
red
acti
vit
y
Patient 11
Patient 11 curve f it
Patient 12
Patient 12 curve f it
Patient 13
Patient 13 curve f it
Clearance at injected tumour
Phase 1 Trial of Systemic TAT for
metastatic melanoma - 2003
• IV administration of AIC through cannula.
• Escalation:, injected activities of 1.25, 2.5,
4, 5.5, 7.5, 12.5, 17.5, 23, 25 mCi.
• Cohort of 3 subjects per dose level.
• Monitor renal damage with serum creatinine
(SC) and glomerular filtration rate (GFR).
• 38 subjects treated to 25 mCi.
Adverse Events?
• No complications of any type or level.
• No change in glomerular filtration rate
(GFR) over 12 months.
• No change in serum creatinine (SC)
over 12 months.
Therapeutic Responses
• 10% partial response (ie tumour
regression).
• 40% stable disease.
• 50% no response (progressive disease).
• 10% long term survival (2-5 y).
Systemic TAT for metastatic
melanoma #7
H&E stain negative for melanoma
Lung, liver and sc tumours #18
• 2 chest lesions disappeared
• Jaw lesion regressed
• 3 lung lesions regressed
• Large liver lesions show stable
disease
Baseline #18
8 weeks #18
• TAT is originally designed for
subclinical, micrometastatic disease.
• Half-life too short (46 min) for AIC to
diffuse into solid tumours (24-48 h).
• Range too short (80 microns) for cross
fire.
• TAT cannot regress tumours!
How did this happen????
α
α
α
Tumour anti-vascular alpha therapy
(TAVAT)
• Leaky gaps between endothelial cells in neogenic
tumour capillaries.
• Pericytes and melanoma cells both express the
targeted MCSP antigen.
• Extra-vascular diffusion of AIC to target the MCSP
antigens on contiguous cells.
• Alpha emission kills endothelial cells.
• Neogenic capillary closes down & tumour regresses.
What next?Increase efficacy and reduce toxicity by:
• CHX-A” chelator for improved stability and
reduced dose to kidneys.
• High specific activity (SA~20 mCi/mg ) to reduce
antigen blocking by unlabeled Mab.
• Fractionated dose over 5 days to allow increased
tumour capillary permeability.
• Escalation of activity/FFM to eliminate over or
under dosing to obese or lean patients.
Pros……..
In spite of ANSTO not supporting the project in 1994:
• Gone from test tube to bed side,
• Achieved world class results,
• Good responses w/o adverse events,
• New protocol approved by SGH-HREC,
• Over 50 publications in TAT,
What could go wrong?
Cons: the perfect storm!Funding
• Low NHMRC rating at 40%!!!!!
• NSWCC does not renew funding support.
• Funds left to continue trial this year?
St George Hospital
• SESIAHS cuts salaried research scientists, offers
Voluntary Redundances.
• Clinical trial manager takes VR.
• Scientists terminated for alleged lack of funds.
• Promoted to Displaced Person!
• Site approval for approved clinical trial not
forthcoming.
Conspiracy or Karma?
• TAT is too good to let bureaucracy kill it off.
• Sydney Rotary Clubs: proposal to sponsor a
patient.
• Overseas PhD students enrolled.
• Displaced Persons must do something….
• Survive until next year’s funding round and the
next election.
The cancer dragon has a new
lease on life!!
TAVAT is the lance to target the
heart of the cancer dragon
Next trial: C595 for MUC1
• Our preclinical data and tumour IHC show
that breast, ovarian, prostate and pancreatic
cancers express the MUC1 receptor.
• Phase 1 clinical trial Bi-213-C595 to target
MUC1 expression in breast, ovarian, prostate
and pancreatic cancers.
• Trial design will follow the melanoma trial.
Other Clinical Trials
• MSK, NY: leukaemia – phase 1 with Bi213 TAT
completed; phase 2 chemo+TAT; phase 1 with
Ac225 trial
• Norway: bone pain - phase 1 &2 with Ac223
• Dusseldorf: lymphoma – phase 1 with Bi213
• Geneva: GBM – phase 1 with Bi213
• Duke Univ: GBM – phase 1 with At211 closed.
Hepatocellular Carcinoma (HCC)
• HCC is a major cancer in Asia, but not Australia.
• PhD student from Sun Yat-Sun University.
• HCC tumour blocks for testing MAbs by IHC.
• Best MAbs chelated with Bi-213 for in vitro
testing in HCC cell lines.
• Efficacy of TAT demonstrated in vivo by
inhibiting tumour growth and regressing tumours.
• Dose limiting organ and max tolerance dose
determined in vivo.